Ethylenediamine derivatives

ABSTRACT

The invention relates a compound represented by the formula (1):  
     Q 1 -Q 2 -C(═O)—N(R 1 )-Q 3 -N(R 2 )-T 1 -Q 4    ( 1 )  
     wherein R 1  and R 2  represent H or the like; Q 1  represents an aromatic ring, heterocyclic ring or the like; Q 2  represents a single bond, aromatic ring, heterocyclic ring or the like; Q 3  represents a group  
                 
 
     or the like, Q 4  represents an aromatic ring, heterocyclic ring or the like; and T 1  represents —CO— or —SO 2 —, and a medicine which comprises the compound and is useful for thrombosis and embolism.

TECHNICAL FIELD

[0001] The present invention relates to novel compounds which inhibitactivated blood coagulation factor X (hereinafter abbreviated as “FXa”)to exhibit a strong anticoagulant effect and can be orally administered,and anticoagulants or agents for preventing and/or treating thrombosisor embolism, which comprise such a novel compound as an activeingredient.

BACKGROUND ART

[0002] In unstable angina, cerebral infarction, cerebral embolism,myocardial infarction, pulmonary infarction, pulmonary embolism,Buerger's disease, deep venous thrombosis, disseminated intravascularcoagulation syndrome, thrombus formation after valve replacement,reocclusion after angioplasty and thrombus formation duringextracorporeal circulation, hypercoagulable state is a pivotal factor.Therefore, there is a demand for development of excellent anticoagulantswhich have good dose responsiveness, long duration, low risk ofhemorrhage and little side effects and fast onset of sufficient effectseven by oral administration (Thrombosis Research, Vol. 68, pp. 507-512,1992).

[0003] Based on the research of anticoagulants worked through variousmechanism of action, it is suggested that FXa inhibitors are promisinganticoagulants. A blood coagulation system comprises a series ofreactions that a great amount of thrombin is produced through anamplification process by multi-stage enzyme reactions to form,insolublefibrin. In an endogenous system, activated factor IX activates intofactor X on a phospholipid membrane in the presence of activated factorVIII and calcium ions after multi-stage reactions subsequent toactivation of a contact factor. In an exogenous system, activated factorVII activates factor X in the presence of a tissue factor. Morespecifically, the activation of the factor X into FXa in the coagulationsystem is a crucial reaction in the formation of thrombin. The activatedfactor X (FXa) limitedly decomposes prothrombin to produce thrombin inthe both systems. Since the produced thrombin activates coagulationfactors in the upper stream, the formation of thrombin is moreamplified. As described above, since the coagulation system in the upperstream of FXa is divided into the endogenous system and the exogenoussystem, production of FXa cannot be sufficiently inhibited by inhibitingenzymes in the coagulation system in the upper stream of FXa, leading toproduction of thrombin. Since the coagulation system comprisesself-amplification reactions, inhibition of the coagulation system canbe more efficiently achieved by inhibiting FXa in the upper stream ofthrombin than the inhibition of thrombin (Thrombosis Research, Vol. 15,pp. 612-629, 1979).

[0004] An another excellent point of FXa inhibitors is a greatdifference between an effective dose in a thrombosis model and a doseelongating bleeding time in an experimental hemorrhagic model. From thisexperimental result, FXa inhibitors are considered to be anticoagulantshaving low risk of hemorrhage.

[0005] Various compounds have been reported as FXa inhibitors. It isknown that antithrombin III and antithrombin III dependentpentasacchrides can generally not inhibit prothrombinase complexes whichplay a practical role in the thrombus formation in a living body(Thrombosis Research, Vol. 68, pp. 507-512, 1992; Journal of ClinicalInvestigation, Vol. 71, pp. 1383-1389, 1983; Mebio, Vol. 14, the Augustnumber, pp. 92-97). In addition, they do not exhibit effectiveness byoral administration. Tick anticoagulant peptide (TAP) (Science, Vol.248, pp. 593-596, 1990) and antistasin (AST) (Journal of BiologicalChemistry, Vol. 263, pp. 10162-10167, 1988) isolated from mites orleeches, which are bloodsuckers, also exhibit an anti-thrombotic effect.However, these compounds are high-molecular weight peptides andunavailable in oral administration. As described above, development ofantithrombin III independent low-molecular weight FXa inhibitors whichdirectly inhibit coagulation factors has been conducted.

[0006] It is therefore an object of the present invention to provide anovel compound which has a strong FXa-inhibiting effect and exhibits ananti-thrombotic effect quickly, sufficiently and persistently by oraladministration.

DISCLOSURE OF THE INVENTION

[0007] The present inventors have investigated synthesis andpharmacological effects of novel FXa inhibitors. As a result,ethylenediamine derivatives, salts thereof, and solvates and N-oxidesthereof, which exhibit strong FXa-inhibiting effect and anticoagulanteffect, have been found. It has also been found that these compoundspromptly, persistently and strongly inhibit FXa and exhibit stronganticoagulant effect and anti-thrombotic effect, and are hence useful asprophylactics and remedies for various diseases based onthromboembolism, thus leading to completion of the present invention.

[0008] This invention provides a compound represented by the generalformula (1):

Q¹-Q²-C(═O)—N(R¹)-Q³-N(R²)-T¹-Q⁴   (1)

[0009] wherein

[0010] R¹ and R², independently of each other, represent a hydrogenatom, hydroxyl group, alkyl group or alkoxy group;

[0011] Q¹ represents a saturated or unsaturated, 5- or 6-membered cyclichydrocarbon group which may be substituted, a saturated or unsaturated,5- or 6-membered heterocyclic group which may be substituted, asaturated or unsaturated, bicyclic or tricyclic fused hydrocarbon groupwhich may be substituted, or a saturated or unsaturated, bicyclic ortricyclic fused heterocyclic group which may be substituted;

[0012] Q² represents a single bond, a linear or branched alkylene grouphaving 1 to 6 carbon atoms, a linear or branched alkenylene group having2 to 6 carbon atoms, a linear or branched alkynylene group having 2 to 6carbon atoms, a group —N(R³)—, in which R³ means a hydrogen atom oralkyl group, a group —N(R⁴)—(CH₂)_(m)—, in which R⁴ means a hydrogenatom or alkyl group, and m is an integer of 1 to 6, a saturated orunsaturated, 5- or 6-membered divalent cyclic hydrocarbon group whichmay be substituted, a saturated or unsaturated, 5- or 6-membereddivalent heterocyclic group which may be substituted, a saturated orunsaturated, divalent bicyclic or tricyclic fused hydrocarbon groupwhich may be substituted, or a saturated or unsaturated, divalentbicyclic or tricyclic fused heterocyclic group which may be substituted;

[0013] Q³ represents a group:

[0014] in which R⁵, R⁶, R⁷ and R⁸, independently of one another, mean ahydrogen atom, hydroxyl group, halogen atom, halogenoalkyl group, cyanogroup, cyanoalkyl group, acyl group, acylalkyl group, alkyl group,alkenyl group, alkynyl group, alkoxy group, alkoxyalkyl group,hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonylgroup, alkoxycarbonylalkyl group, carbamoyl group, N-alkylcarbamoylgroup, N,N-dialkyl-carbamoyl group, carbamoylalkyl group,N-alkylcarbamoylalkyl group, N,N-dialkylcarbamoylalkyl group, arylgroup, aralkyl group, heteroaryl group or heteroarylalkyl group, or thefollowing group:

[0015] in which Q⁵ means an alkylene group having 1 to 8 carbon atoms oran alkenylene group having 2 to 8 carbon atoms, and R⁹ and R¹⁰ aresubstituents on carbon atom(s) of a ring comprising Q⁵ and areindependently of each other a hydrogen atom, hydroxyl group, alkylgroup, alkenyl group, alkynyl group, halogen atom, halogenoalkyl group,cyano group, cyanoalkyl group, amino group, aminoalkyl group,N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group,acylalkyl group, acylamino group which may be substituted, alkoxyiminogroup, hydroxyimino group, acylaminoalkyl group, alkoxy group,alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkylgroup, alkoxycarbonyl group, alkoxycarbonylalkyl group,alkoxycarbonylalkylamino group, carboxyalkylamino group,alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoylgroup, N-alkylcarbamoyl group which may have a substituent on the alkylgroup, N,N-dialkylcarbamoyl group which may have a substituent on thealkyl group, N-alkenyl-carbamoyl group, N-alkenylcarbamoylalkyl group,N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group,N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group,N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group,carbazoyl group which may be substituted by 1 to 3 alkyl groups,alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-memberednitrogen-containing heterocyclic carbonyl group which may besubstituted, 3- to 6-membered nitrogen-containing heterocycliccarbonylalkyl group which may be substituted, carbamoylalkyl group,N-alkylcarbamoylalkyl group which may have a substituent on the alkylgroup, N,N-dialkylcarbamoylalkyl group which may have a substituent onthe alkyl group, carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkylgroup, N,N-dialkylcarbamoyl-oxyalkyl group, 3- to 6-memberednitrogen-containing heterocyclic carbonyloxyalkyl group which may besubstituted, aryl group, aralkyl group, heteroaryl group,heteroarylalkyl group, alkylsulfonylamino group, arylsulfonylaminogroup, alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl group,alkylsulfonylaminocarbonyl group, arylsulfonylaminocarbonyl group,alkylsulfonylaminocarbonylalkyl group, arylsulfonylaminocarbonylalkylgroup, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxygroup, acyloxy group or acyloxyalkyl group, or R⁹ and R¹⁰, together witheach other, denote an alkylene group having 1 to 5 carbon atoms,alkenylene group having 2 to 5 carbon atoms, alkylenedioxy group having1 to 5 carbon atoms or carbonyldioxy group;

[0016] Q⁴ represents an aryl group which may be substituted, anarylalkenyl group which may be substituted, a heteroaryl group which maybe substituted, a heteroarylalkenyl group which may be substituted, asaturated or unsaturated, bicyclic or tricyclic fused hydrocarbon groupwhich may be substituted, or a saturated or unsaturated, bicyclic ortricyclic fused heterocyclic group which may be substituted; and

[0017] T¹ represents a carbonyl or sulfonyl group; a salt thereof, asolvate thereof, or an N-oxide thereof.

[0018] This invention also provides a medicine comprising the compounddescried above, the salt thereof, the solvate thereof, or N-oxidethereof as an active ingredient.

[0019] This invention further provides a medicinal compositioncomprising the compound descried above, the salt thereof, the solvatethereof, or N-oxide thereof and a pharmaceutically acceptable carrier.

[0020] This invention still further provides use of the compounddescried above, the salt thereof, the solvate thereof, or N-oxidethereof for preparation of a medicine.

[0021] This invention yet still further provides a method for treatingthrombosis or embolism, which comprises administering the compounddescried above, the salt thereof, the solvate thereof, or N-oxidethereof.

[0022] This invention yet still further provides a method for treatingcerebral infarction, cerebral embolism, myocardial infarction, anginapectoris, pulmonary infarction, pulmonary embolism, Buerger's disease,deep venous thrombosis, disseminated intravascular coagulation syndrome,thrombus formation after valve or joint replacement, thrombus formationand reocclusion after angioplasty, systemic inflammatory reactionsyndrome (SIRS), multiple organ disease syndrome (MODS), thrombusformation during extracorporeal circulation, or blood clotting uponblood gathering, which comprises administering the compound descriedabove, the salt thereof, the solvate thereof, or N-oxide thereof. Thisinvention yet still further provides an intermediate useful forpreparing the compound (1) according to the present invention.

BEST MODE FOR CARRYING OUT THE INVENTION

[0023] Substituents in the ethylenediamine derivatives according to thepresent invention represented by the general formula (1) willhereinafter be described.

[0024] <On Group Q⁴>

[0025] The group Q⁴ means an aryl group which may be substituted, anarylalkenyl group which may be substituted, a heteroaryl group which maybe substituted, a heteroarylalkenyl group which may be substituted, asaturated or unsaturated, bicyclic or tricyclic fused hydrocarbon groupwhich may be substituted, or a saturated or unsaturated, bicyclic ortricyclic fused heterocyclic group which may be substituted.

[0026] In the group Q⁴, the aryl group may include aryl groups having 6to 14 carbon atoms, for example, phenyl, naphthyl, anthryl andphenanthryl groups.

[0027] The arylalkenyl group means a group formed by an aryl grouphaving 6 to 14 carbon atoms and an alkenylene group having 2 to 6 carbonatoms, and examples thereof may include a styryl group.

[0028] The heteroaryl group means a monovalent aromatic group having atleast one heteroatom selected from oxygen, sulfur and nitrogen atoms,and examples thereof may include 5- or 6-membered heteroaryl groups, forexample, pyridyl, furyl, thienyl, pyrimidinyl and tetrazolyl groups.

[0029] The heteroarylalkenyl group means a group formed by theabove-described heteroaryl group and an alkenylene group having 2 to 6carbon atoms, and examples thereof may include thienylethenyl andpyridylethenyl groups.

[0030] The saturated or unsaturated, bicyclic or tricyclic fusedhydrocarbon group means a monovalent group derived from a saturated orunsaturated, bicyclic or tricyclic fused hydrocarbon. The saturated orunsaturated, bicyclic or tricyclic fused hydrocarbon denotes a bicyclicor tricyclic fused hydrocarbon formed by fusing 2 or 3 saturated orunsaturated, 5- or 6-membered cyclic hydrocarbons which are the same ordifferent from each other. In this case, examples of the saturated orunsaturated, 5- or 6-membered cyclic hydrocarbons may includecyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene andbenzene. Specific examples of the saturated or unsaturated, bicyclic ortricyclic fused hydrocarbon group may include indenyl, indanyl andtetrahydronaphthyl groups. Incidentally, the position of the saturatedor unsaturated, bicyclic or tricyclic fused hydrocarbon group bonded toT¹ in the general formula (1) is not particularly limited.

[0031] The saturated or unsaturated, bicyclic or tricyclic fusedheterocyclic group means a monovalent group derived from a saturated orunsaturated, bicyclic or tricyclic fused heterocyclic ring. Thesaturated or unsaturated, bicyclic or tricyclic fused heterocyclic ringdenotes the following heterocyclic ring {circle over (1)}, {circle over(2)} or {circle over (3)}:

[0032] {circle over (1)}: a bicyclic or tricyclic fused heterocyclicring formed by fusing 2 or 3 saturated or unsaturated, 5- or 6-memberedheterocyclic rings which are the same or different from each other;

[0033] {circle over (2)}: a bicyclic or tricyclic fused heterocyclicring formed by fusing a saturated or unsaturated, 5- or 6-memberedheterocyclic ring with 1 or 2 saturated or unsaturated, 5- or 6-memberedcyclic hydrocarbons; or

[0034] {circle over (3)}: a tricyclic fused heterocyclic ring formed byfusing 2 saturated or unsaturated, 5- or 6-membered heterocyclic ringswith a saturated or unsaturated, 5- or 6-membered cyclic hydrocarbon.

[0035] The position of the saturated or unsaturated, bicyclic ortricyclic fused heterocyclic group bonded to T¹ in the general formula(1) is not particularly limited.

[0036] The saturated or unsaturated, 5- or 6-membered heterocyclic ringdenotes a heterocyclic ring having at least one heteroatom selected fromoxygen, sulfur and nitrogen atoms, and specific examples thereof mayinclude furan, pyrrole, thiophene, pyrazole, imidazole, oxazole,oxazolidine, thiazole, thiadiazole, furazane, pyrane, pyridine,pyrimidine, pyridazine, pyrrolidine, piperazine, piperidine, oxazine,oxadiazine, morpholine, thiazine, thiadiazine, thiomorpholine,tetrazole, triazole and triazine. The saturated or unsaturated, 5- or6-membered cyclic hydrocarbon denotes the same saturated or unsaturated,5- or 6-membered cyclic hydrocarbon as shown in the description of thesaturated or unsaturated, bicyclic or tricyclic fused hydrocarbon group.Specific examples of the saturated or unsaturated, bicyclic or tricyclicfused heterocyclic group may include benzofuryl, benzothienyl, indolyl,indolinyl, isoindolyl, indazolyl, quinolyl, tetrahydroquinolyl,isoquinolyl, tetrahydroisoquinolyl, quinazolyl, dihydroquinazolyl,tetrahydroquinazolyl, quinoxalyl, tetrahydroquinoxalyl, cinnolyl,tetrahydrocinnolyl, indolizinyl, tetrahydroindolizinyl, benzothiazolyl,tetrahydrobenzothiazolyl, naphthyridinyl, tetrahydronaphthyridinyl,thienopyridyl, tetrahydrothienopyridyl, thiazolopyridyl,tetrahydrothiazolopyridyl, thiazolopyridazinyl,tetrahydrothiazolopyridazinyl, pyrrolopyridyl, tetrahydropyrrolopyridyl,pyrrolopyrimidinyl, dihydropyrrolopyrimidinyl, dihydropyridoquinazolyl,pyridopyrimidinyl, tetrahydropyridopyrimidinyl, pyranothiazolyl,dihydropyranothiazolyl, furopyridyl, tetrahydrofuropyridyl,oxazolopyridyl, tetrahydrooxazolopyridyl, oxazolopyridazinyl,tetrahydrooxazolopyridazinyl, pyrrolothiazolyl, dihydropyrrolothiazolyl,pyrrolooxazolyl and dihydropyrrolooxazolyl groups. No particularlimitation is imposed on the fusing form of the fused heterocyclicgroup. For example, the naphthyridinyl group may be any of 1,5-, 1,6-,1,7-, 1,8-, 2,6- and 2,7-naphthyridinyl groups, the thienopyridyl groupmay be any of thieno-[2,3-b]pyridyl, thieno[2,3-c]pyridyl,thieno[3,2-b]-pyridyl, thieno[3,2-c]pyridyl, thieno[3,4-b]pyridyl andthieno[3,4-c]pyridyl groups, the thiazolopyridyl group may be any ofthiazolo[4,5-b]pyridyl, thiazolo[4,5-c]-pyridyl, thiazolo[5,4-b]pyridyl,thiazolo[5,4-c]pyridyl, thiazolo[3,4-a]pyridyl andthiazolo[3,2-a]pyridyl groups, the thiazolopyridazinyl group may be anyof thiazolo-[4,5-c]pyridazinyl, thiazolo[4,5-d]pyridazinyl,thiazolo[5,4-c]pyridazinyl and thiazolo[3,2-b]-pyridazinyl groups, thepyrrolopyridyl may be any of pyrrolo[2,3-b]pyridyl,pyrrolo[2,3-c]pyridyl, pyrrolo[3,2-b]pyridyl, pyrrolo[3,2-c]pyridyl,pyrrolo-[3,4-b]pyridyl and pyrrolo[3,4-c]pyridyl group, thepyridopyrimidinyl group may be any of pyrido[2,3-d]-pyrimidinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]-pyrimidinyl,pyrido[4,3-d]pyrimidinyl, pyrido[1,2-c]pyrimidinyl andpyrido[1,2-a]pyrimidinyl groups, the pyranothiazolyl group may be any ofpyrano[2,3-d]-thiazolyl, pyrano[4,3-d]thiazolyl, pyrano[3,4-d]-thiazolyland pyrano[3,2-d]thiazolyl groups, the furopyridyl group may be any offuro[2,3-b]pyridyl, furo[2,3-c]pyridyl, furo[3,2-b]pyridyl,furo[3,2-c]-pyridyl, furo[3,4-b]pyridyl and furo[3,4-c]pyridyl groups,the oxazolopyridyl group may be any of oxazolo-[4,5-b]pyridyl,oxazolo[4,5-c]pyridyl, oxazolo[5,4-b]-pyridyl, oxazolo[5,4-c]pyridyl,oxazolo[3,4-a]pyridyl and oxazolo[3,2-a]pyridyl groups, theoxazolopyridazinyl group may be any of oxazolo[4,5-c]pyridazinyl,oxazolo[4,5-d]pyridazinyl, oxazolo[5,4-c]pyridazinyl andoxazolo[3,4-b]pyridazinyl groups, the pyrrolothiazolyl group may be anyof pyrrolo[2,1-b]thiazolyl, pyrrolo-[1,2-c]thiazolyl,pyrrolo[2,3-d]thiazolyl, pyrrolo-[3,2-d]thiazolyl andpyrrolo[3,4-d]thiazolyl groups, and the pyrrolooxazolyl group may be anyof pyrrolo[2,1-b]-oxazolyl, pyrrolo[1,2-c]oxazolyl,pyrrolo[2,3-d]oxazolyl, pyrrolo[3,2-d]oxazolyl andpyrrolo[3,4-d]oxazolyl groups. Other fusing forms than these may beallowed.

[0037] The above-described aryl groups, heteroaryl groups, arylalkenylgroup, heteroarylalkenyl groups, saturated or unsaturated, bicyclic ortricyclic fused hydrocarbon groups and saturated or unsaturated,bicyclic or tricyclic fused heterocyclic groups may each have 1 to 3substituents. Examples of the substituents may include a hydroxyl group,halogen atoms such as fluorine atom, chlorine atom, bromine atom andiodine atom, halogenoalkyl groups having 1 to 6 carbon atoms, and 1 to 3halogen as substituents, an amino group, a cyano group, aminoalkylgroups, a nitro group, hydroxyalkyl groups (for example, hydroxymethylgroup, 2-hydroxyethyl group, etc.), alkoxyalkyl groups (for example,methoxymethyl group, 2-methoxyethyl group, etc.), a carboxyl group,carboxyalkyl groups (for example, carboxymethyl group, 2-carboxyethylgroup, etc.), alkoxycarbonylalkyl groups (for example,methoxycarbonylmethyl group, ethoxycarbonylmethyl group, etc.), acylgroups (for example, acetyl group, propionyl group, etc.), an amidinogroup, a hydroxyamidino group, linear, branched or cyclic alkyl groups(for example, methyl group, ethyl group, etc.) having 1 to 6 carbonatoms, linear, branched or cyclic alkoxy groups (for example, methoxygroup, ethoxy group, etc.) having 1 to 6 carbon atoms, amidino groups(for example, methoxycarbonylamidino group, ethoxycarbonylamidino group,etc.) substituted by linear, branched or cyclic alkoxycarbonyl grouphaving 2 to 7 carbon atoms, linear, branched or cyclic alkenyl groups(for example, vinyl group, allyl group, etc.) having 2 to 6 carbonatoms, linear or branched alkynyl groups (for example, ethynyl group,propynyl group, etc.) having 2 to 6 carbon atoms, linear, branched orcyclic alkoxycarbonyl groups (for example, methoxycarbonyl group,ethoxycarbonyl group, etc.) having 2 to 6 carbon atoms, a carbamoylgroup, mono- or di-alkylamino groups (for example, ethylamino,dimethylamino and methylethylamino groups) substituted by 1 or 2 linear,branched or cyclic alkyl groups having 1 to 6 carbon atoms, and 5- or6-membered nitrogen-containing heterocyclic groups (for example,pyrrolidino group, piperidino group, piperazino group, morpholino group,etc.).

[0038] As the group Q⁴, are preferred the following 5 groups among theabove-described groups. Namely,

[0039] wherein R¹¹ and R¹², independently of each other, represent ahydrogen atom, cyano group, halogen atom, alkyl group, hydroxyalkylgroup, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkylgroup, acyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, orphenyl group which may be substituted by a cyano group, hydroxyl group,halogen atom, alkyl group or alkoxy group, and R¹³ and R¹⁴,independently of each other, represent a hydrogen atom, hydroxyl group,nitro group, cyano group, halogen atom, alkyl group, alkenyl group,alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group,alkoxyalkyl group, carboxyl group, carboxyalkyl group, carbamoyl group,alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group;

[0040] wherein R¹⁵, R¹⁶ and R¹⁷, independently of one another, representa hydrogen atom, hydroxyl group, nitro group, cyano group, halogen atom,alkyl group, alkenyl group, alkynyl group, halogenoalkyl group,hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group,carboxyalkyl group, acyl group, carbamoyl group, alkoxycarbonyl group,amidino group or alkoxycarbonylalkyl group;

[0041] wherein X¹ represents CH₂, CH, NH, NOH, N, O or S, and R¹⁸, R¹⁹and R²⁰, independently of one another, represent a hydrogen atom,hydroxyl group, nitro group, cyano group, halogen atom, alkyl group,alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group,alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group,acyl group, carbamoyl group, alkoxycarbonyl group, amidino group oralkoxycarbonylalkyl group;

[0042] wherein X² represents NH, N, O or S, X³ represents N, C or CH, X⁴represents N, C or CH, and R²¹ and R²², independently of each other,represent a hydrogen atom, hydroxyl group, nitro group, cyano group,halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkylgroup, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxylgroup, carboxyalkyl group, acyl group, carbamoyl group, alkoxycarbonylgroup, amidino group or alkoxycarbonylalkyl group; and

[0043] wherein N indicates that any one of carbon atoms of the ringsubstituted by R²³ has been substituted by a nitrogen atom, and R²³, R²⁴and R²⁵, independently of one another, represent a hydrogen atom,hydroxyl group, nitro group, cyano group, halogen atom, alkyl group,alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group,alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group,acyl group, carbamoyl group, alkoxycarbonyl group, amidino group oralkoxycarbonylalkyl group.

[0044] These groups will hereinafter be described.

[0045] In the description of R¹¹ to R²⁵, the halogen atom is a fluorine,chlorine, bromine or iodine atom, the alkyl group is a linear, branchedor cyclic alkyl group having 1 to 6 carbon atoms, the alkenyl group is alinear, branched or cyclic alkenyl groups having 2 to 6 carbon atoms,the alkynyl group is a linear or branched alkynyl groups having 2 to 6carbon atoms, the hydroxyalkyl group means the above-described alkylgroup substituted by a hydroxyl group, the alkoxy group is a linear,branched or cyclic alkoxy group having 1 to 6 carbon atoms, thealkoxyalkyl group means the above-described alkyl group substituted bythe above-described alkoxy group, the carboxyalkyl group means theabove-described alkyl group substituted by a carboxyl group, the acylgroup is an alkanoyl group having 1 to 6 carbon atom, an aroyl groupsuch as a benzoyl or naphthoyl group, or an arylalkanoyl group with theabove-described aryl group substituted on the above-described alkanoylgroup, the alkoxycarbonyl group is a group composed of theabove-described alkoxy group and a carbonyl group, thealkoxycarbonylalkyl group means the above-described alkyl groupsubstituted by the above-described alkoxycarbonyl group, and thehalogenoalkyl group means the above-described alkyl group substituted by1 to 3 halogen atoms. Incidentally, in the above description, noparticular limitation is imposed on the substituting position.

[0046] In the following group:

[0047] wherein R¹¹, R¹², R¹³ and R¹⁴ have the same meanings as definedabove, and numerals 1 to 6 indicate positions, R¹¹ and R¹² arepreferably hydrogen atoms or alkyl groups. In the case of the alkylgroup, a methyl group is preferred. R¹³ and R¹⁴ are, independently ofeach other, preferably a hydrogen atom, cyano group, halogen atom, alkylgroup, alkenyl group, alkynyl group or halogenoalkyl group. It ispreferable that one of R¹³ and R¹⁴ is a hydrogen atom, and the other isa cyano group, halogen atom, alkyl group, alkenyl group, alkynyl groupor halogenoalkyl group. Among others, it is particularly preferred thatthe other group be a halogen atom or alkynyl group. In this case, thehalogen atom is preferably a fluorine, chlorine or bromine atom. As thealkynyl group, is particularly preferred an ethynyl group. As specificpreferable examples of the group represented by the above formula, maybe mentioned chlorostyryl, fluorostyryl, bromostyryl and ethynylstyrylgroups. The position substituted by the halogen atom or alkynyl group isparticularly preferably a 4-position in the above formula. As specificpreferable examples thereof, may be mentioned 4-chlorostyryl,4-fluorostyryl, 4-bromostyryl and 4-ethynylstyryl groups.

[0048] In the following group:

[0049] wherein R¹⁵, R¹⁶ and R¹⁷ have the same meanings as defined above,and numerals 1 to 8 indicate positions, R¹⁵, R¹⁶ and R¹⁷ are,independently of one another, preferably a hydrogen atom, cyano group,halogen atom, alkyl group, alkenyl group, alkynyl group or halogenoalkylgroup. R¹⁵ is preferably a hydrogen atom, alkyl group, halogen atom orhydroxyl group, with a hydrogen atom particularly preferred. It ispreferable that one of R¹⁶ and R¹⁷ is a hydrogen atom, and the other isa cyano group, halogen atom, alkyl group, alkenyl group, alkynyl groupor halogenoalkyl group. Among others, it is particularly preferred thatthe other group be a halogen atom or alkynyl group. In this case, thehalogen atom is preferably a fluorine, chlorine or bromine atom. As thealkynyl group, is preferred an ethynyl group. In the naphthyl group, a2-naphthyl group is preferred to a 1-naphthyl group. In the case of the2-naphthyl group, a position substituted by a halogen atom or alkynylgroup is preferably a 6- or 7-position in the above formula, with a6-position being most preferred. These naphthyl groups are preferblysubstituted by a chlorine, fluorine or bromine atom, an alkynyl group,or the like, with a group having a substituents such as a chlorine,fluorine or bromine atom, an alkynyl group, or the like at theabove-described position in the above formula being particularlypreferred. As specific preferable examples thereof, may be mentioned6-chloro-2-naphthyl, 6-fluoro-2-naphthyl, 6-bromo-2-naphthyl,6-ethynyl-2-naphthyl, 7-chloro-2-naphthyl, 7-fluoro-2-naphthyl,7-bromo-2-naphthyl and 7-ethynyl-2-naphthyl groups.

[0050] In the following group:

[0051] wherein X¹, R¹⁸, R¹⁹ and R²⁰ have the same meanings as definedabove, and numerals 4 to 7 indicate positions, X¹ is preferably NH, NOH,N, O or S, with NH, O or S being particularly preferred. R¹⁸ ispreferably a hydrogen atom, and R¹⁹ and R²⁰ are, independently of eachother, preferably a hydrogen atom, cyano group, halogen atom, alkylgroup, alkenyl group, alkynyl group or halogenoalkyl group. It ispreferable that one of R¹⁹ and R²⁰ is a hydrogen or a halogen atom,preferably fluorine atom, and the other is a cyano group, halogen atom,alkyl group, alkenyl group, alkynyl group or halogenoalkyl group. Amongothers, it is particularly preferred that the other group be a halogenatom, an alkyl or alkynyl group. In this case, the halogen atom ispreferably a fluorine, chlorine or bromine atom. As the alkyl group, ispreferred a methyl group. As the alkynyl group, is preferred an ethynylgroup. The position substituted by the halogen atom, alkyl group oralkynyl group is preferably a 5- or 6-position in the above formula. Asspecific preferable examples of the group represented by the aboveformula, may be mentioned 5-chloroindolyl, 5-fluoroindolyl,5-bromoindolyl, 5-ethynylindolyl, 5-methylindolyl,5-chloro-4-fluoroindolyl, 6-chloroindolyl, 6-fluoroindolyl,6-bromoindolyl, 6-ethynylindolyl, 6-methylindolyl, 5-chlorobenzothienyl,5-fluorobenzothienyl, 5-bromo-benzothienyl, 5-ethynylbenzothienyl,5-methyl-benzothienyl, 5-chloro-4-fluorobenzothienyl,6-chlorobenzothienyl, 6-fluorobenzothienyl, 6-bromobenzothienyl,6-ethynylbenzothienyl, 6-methylbenzothienyl, 5-chlorobenzofuryl,5-fluorobenzofuryl, 5-bromobenzofuryl, 5-ethynylbenzofuryl,5-methylbenzofuryl, 5-chloro-4-fluorobenzofuryl, 6-chlorobenzofuryl,6-fluorobenzofuryl, 6-bromobenzofuryl, 6-ethynylbenzofuryl and6-methylbenzofuryl groups. The position of the above-describedsubstituent group bonded to T¹ is not particularly limited. Morepreferred are 5-chloroindol-2-yl, 5-fluoroindol-2-yl, 5-bromoindol-2-yl,5-ethynylindol-2-yl, 5-methylindol-2-yl, 5-chloro-4-fluoroindol-2-yl,6-chloroindol-2-yl, 6-fluoroindol-2-yl, 6-bromoindol-2-yl,6-ethynylindol-2-yl, 6-methylindol-2-yl, 5-chloroindol-3-yl,5-fluoroindol-3-yl, 5-bromoindol-3-yl, 5-ethynylindol-3-yl,5-methylindol-3-yl, 5-chloro-4-fluoroindol-3-yl, 6-chloroindol-3-yl,6-fluoroindol-3-yl, 6-bromoindol-3-yl, 6-ethynylindol-3-yl,6-methylindol-3-yl, 5-chlorobenzothiophen-2-yl,5-fluorobenzothiophen-2-yl, 5-bromobenzothiophen-2-yl,5-ethynylbenzothiophen-2-yl, 5-methylbenzothiophen-2-yl,5-chloro-4-fluorobenzothiophen-2-yl, 6-chlorobenzothiophen-2-yl,6-fluorobenzothiophen-2-yl, 6-bromobenzothiophen-2-yl,6-ethynylbenzothiophen-2-yl, 6-methylbenzothiophen-2-yl,5-chlorobenzothiophen-3-yl, 5-fluorobenzothiophen-3-yl,5-bromobenzothiophen-3-yl, 5-ethynylbenzothiophen-3-yl,5-methylbenzothiophen-3-yl, 5-chloro-4-fluorobenzothiophen-3-yl,6-chlorobenzothiophen-3-yl, 6-fluorobenzothiophen-3-yl,6-bromobenzothiophen-3-yl, 6-ethynylbenzothiophen-3-yl,6-methylbenzothiophen-3-yl, 5-chlorobenzofuran-2-yl,5-fluorobenzofuran-2-yl, 5-bromobenzofuran-2-yl,5-ethynylbenzofuran-2-yl, 5-methylbenzofuran-2-yl,5-chloro-4-fluorobenzofuran-2-yl, 6-chlorobenzofuran-2-yl,6-fluorobenzofuran-2-yl, 6-bromobenzofuran-2-yl,6-ethynylbenzofuran-2-yl, 6-methylbenzofuran-2-yl,5-chlorobenzofuran-3-yl, 5-fluorobenzofuran-3-yl,5-bromobenzofuran-3-yl, 5-ethynylbenzofuran-3-yl,5-methylbenzofuran-3-yl, 5-chloro-4-fluorobenzofuran-3-yl,6-chlorobenzofuran-3-yl, 6-fluorobenzofuran-3-yl,6-bromobenzofuran-3-yl, 6-ethynylbenzofuran-3-yl and6-methylbenzofuran-3-yl groups, with 5-chloroindol-2-yl,5-fluoroindol-2-yl, 5-bromoindol-2-yl, 5-ethynylindol-2-yl,5-methyindol-2-yl, 5-chloro-4-fluoroindol-2-yl, 6-chloroindol-2-yl,6-fluoroindol-2-yl, 6-bromoindol-2-yl, 6-ethynylindol-2-yl,6-methyindol-2-yl, 5-chlorobenzothiophen-2-yl,5-fluorobenzothiophen-2-yl, 5-bromobenzothiophen-2-yl,5-ethynylbenzothiophen-2-yl, 5-methylbenzothiophen-2-yl,5-chloro-4-fluorobenzothiophen-2-yl, 6-chlorobenzothiophen-2-yl,6-fluorobenzothiophen-2-yl, 6-bromobenzothiophen-2-yl,6-ethynylbenzothiophen-2-yl, 6-methylbenzothiophen-2-yl,5-chlorobenzofuran-2-yl, 5-fluorobenzofuran-2-yl,5-bromobenzofuran-2-yl, 5-ethynylbenzofuran-2-yl,5-methylbenzofuran-2-yl, 5-chloro-4-fluorobenzofuran-2-yl,6-chlorobenzofuran-2-yl, 6-fluorobenzofuran-2-yl,6-bromobenzofuran-2-yl, 6-ethynylbenzofuran-2-yl and6-methylbenzofuran-2-yl groups being particularly preferred.

[0052] In the following group:

[0053] wherein X², X³, X⁴, R²¹ and R²² have the same meanings as definedabove, and numerals 4 to 7 indicate positions, any one of X³ and X⁴ ispreferably CH or C, particularly preferably C. R²¹ and R²² are,independently of each other, preferably a hydrogen atom, cyano group,halogen atom, alkyl group, alkenyl group, alkynyl group or halogenoalkylgroup. It is preferable that one of R²¹ and R²² is a hydrogen atom, andthe other is a cyano group, halogen atom, alkyl group, alkenyl group,alkynyl group or halogenoalkyl group. Among others, it is particularlypreferred that the other group be a halogen atom or alkynyl group. Inthis case, the halogen atom is preferably a fluorine, chlorine orbromine atom. As the alkynyl group, is preferred an ethynyl group. Theposition substituted by the halogen atom or alkynyl group is preferablya 5- or 6-position in the above formula. As specific preferable examplesof the group represented by the above formula, may be mentioned5-chloroindazolyl, 5-fluoroindazolyl, 5-bromoindazolyl,5-ethynylindazolyl, 6-chloroindazolyl, 6-fluoroindazolyl,6-bromoindazolyl, 6-ethynylindazolyl, 5-chlorobenzimidazolyl,5-fluorobenzimidazolyl, 5-bromobenzimidazolyl, 5-ethynylbenzimidazolyl,6-chlorobenzimidazolyl, 6-fluorobenzimidazolyl, 6-bromobenzimidazolyl,6-ethynylbenzimidazolyl, 5-chlorobenzothiazolyl, 5-fluorobenzothiazolyl,5-bromobenzothiazolyl, 5-ethynylbenzothiazolyl, 6-chlorobenzothiazolyl,6-fluorobenzothiazolyl, 6-bromobenzothiazolyl, 6-ethynylbenzothiazolyl,5-chlorobenzoxazolyl, 5-fluorobenzoxazolyl, 5-bromobenzoxazolyl,5-ethynylbenzoxazolyl, 6-chlorobenzoxazolyl, 6-fluorobenzoxazolyl,6-bromobenzoxazolyl, 6-ethynylbenzoxazolyl, 5-chlorobenzisothiazolyl,5-fluorobenzisothiazolyl, 5-bromobenzisothiazolyl,5-ethynylbenzisothiazolyl, 6-chlorobenzisothiazolyl,6-fluorobenzisothiazolyl, 6-bromobenzisothiazolyl,6-ethynylbenzisothiazolyl, 5-chlorobenzisoxazolyl,5-fluorobenzisoxazolyl, 5-bromobenzisoxazolyl, 5-ethynylbenzisoxazolyl,6-chlorobenzisoxazolyl, 6-fluorobenzisoxazolyl, 6-bromobenzisoxazolyland 6-ethynylbenzisoxazolyl groups. The position of the above-describedsubstituent group bonded to T¹ is not particularly limited. Morepreferred are 5-chloroindazol-3-yl, 5-fluoroindazol-3-yl,5-bromoindazol-3-yl, 5-ethynylindazol-3-yl, 6-chloroindazol-3-yl,6-fluoroindazol-3-yl, 6-bromoindazol-3-yl, 6-ethynylindazol-3-yl,5-chlorobenzimidazol-2-yl, 5-fluorobenzimidazol-2-yl,5-bromobenzimidazol-2-yl, 5-ethynylbenzimidazol-2-yl,6-chlorobenzimidazol-2-yl, 6-fluorobenzimidazol-2-yl,6-bromobenzimidazol-2-yl, 6-ethynylbenzimidazol-2-yl,5-chlorobenzothiazol-2-yl, 5-fluorobenzothiazol-2-yl,5-bromobenzothiazol-2-yl, 5-ethynylbenzothiazol-2-yl,6-chlorobenzothiazol-2-yl, 6-fluorobenzothiazol-2-yl,6-bromobenzothiazol-2-yl, 6-ethynylbenzothiazol-2-yl,5-chlorobenzoxazol-2-yl, 5-fluorobenzoxazol-2-yl,5-bromobenzoxazol-2-yl, 5-ethynylbenzoxazol-2-yl,6-chlorobenzoxazol-2-yl, 6-fluorobenzoxazol-2-yl,6-bromobenzoxazol-2-yl, 6-ethynylbenzoxazol-2-yl,5-chlorobenzisothiazol-3-yl, 5-fluorobenzisothiazol-3-yl,5-bromobenzisothiazol-3-yl, 5-ethynylbenzisothiazol-3-yl,6-chlorobenzisothiazol-3-yl, 6-fluorobenzisothiazol-3-yl,6-bromobenzisothiazol-3-yl, 6-ethynylbenzisothiazol-3-yl,5-chlorobenzisoxazol-3-yl, 5-fluorobenzisoxazol-3-yl,5-bromobenzisoxazol-3-yl, 5-ethynylbenzisoxazol-3-yl,6-chlorobenzisoxazol-3-yl, 6-fluorobenzisoxazol-3-yl,6-bromobenzisoxazol-3-yl and 6-ethynylbenzisoxazol-3-yl groups, with5-chlorobenzimidazol-2-yl, 5-fluorobenzimidazol-2-yl,5-bromobenzimidazol-2-yl, 5-ethynylbenzimidazol-2-yl,6-chlorobenzimidazol-2-yl, 6-fluorobenzimidazol-2-yl,6-bromobenzimidazol-2-yl, 6-ethynylbenzimidazol-2-yl,5-chlorobenzothiazol-2-yl, 5-fluorobenzothiazole-2-yl,5-bromobenzothiazol-2-yl, 5-ethynylbenzothiazole-2-yl,6-chlorobenzothiazol-2-yl, 6-fluorobenzothiazole-2-yl,6-bromobenzothiazol-2-yl, 6-ethynylbenzothiazole-2-yl,5-chlorobenzoxazol-2-yl, 5-fluorobenzoxazol-2-yl,5-bromobenzoxazol-2-yl, 5-ethynylbenzoxazol-2-yl,6-chlorobenzoxazol-2-yl, 6-fluorobenzoxazol-2-yl, 6-bromobenzoxazol-2-yland 6-ethynylbenzoxazol-2-yl groups being particularly preferred.

[0054] In the following group:

[0055] wherein N indicates that any one of carbon atoms of the ringsubstituted by R²³ has been substituted by a nitrogen atom, R²³, R²⁴ andR²⁵ have the same meanings as defined above, and numerals 5 to 8indicate positions, R²³, R²⁴ and R²⁵ are, independently of each other,preferably a hydrogen atom, cyano group, halogen atom, alkyl group,alkenyl group, alkynyl group or halogenoalkyl group. R²³ is particularlypreferably a hydrogen atom. It is preferable that one of R²⁴ and R²⁵ isa hydrogen atom, and the other is a cyano group, halogen atom, alkylgroup, alkenyl group, alkynyl group or halogenoalkyl group. Amongothers, it is particularly preferred that the other group be a halogenatom or alkynyl group. In this case, the halogen atom is preferably afluorine, chlorine or bromine atom. As the alkynyl group, is preferredan ethynyl group. The position substituted by the halogen atom oralkynyl group is preferably a 6- or 7-position in the above formula. Asspecific preferable examples thereof, may be mentioned quinolinyl andisoquinolinyl groups. More preferred are 6-chloroquinolinyl,6-fluoroquinolinyl, 6-bromoquinolinyl, 6-ethynylquinolinyl,6-chloroisoquinolinyl, 6-fluoroisoquinolinyl, 6-bromoisoquinolinyl and6-ethynylisoquinolinyl groups, with 6-chloroquinolin-2-yl,6-fluoroquinolin-2-yl, 6-bromoquinolin-2-yl, 6-ethynylquinolin-2-yl,6-chloroquinolin-3-yl, 6-fluoroquinolin-3-yl, 6-bromoquinolin-3-yl,6-ethynylquinolin-3-yl, 7-chloroquinolin-2-yl, 7-fluoroquinolin-2-yl,7-bromoquinolin-2-yl, 7-ethynylquinolin-2-yl, 7-chloroquinolin-3-yl,7-fluoroquinolin-3-yl, 7-bromoquinolin-3-yl, 7-ethynylquinolin-3-yl,6-chloroisoquinolin-3-yl, 6-fluoroisoquinolin-3-yl,6-bromoisoquinolin-3-yl, 6-ethynylisoquinolin-3-yl,7-chloroisoquinolin-3-yl, 7-fluoroisoquinolin-3-yl,7-bromoisoquinolin-3-yl and 7-ethynylisoquinolin-3-yl groups beingparticularly preferred.

[0056] <On Group Q¹>

[0057] In the present invention, Q¹ means a saturated or unsaturated, 5-or 6-membered cyclic hydrocarbon group which may be substituted, asaturated or unsaturated, 5- or 6-membered heterocyclic group which maybe substituted, a saturated or unsaturated, bicyclic or tricyclic fusedhydrocarbon group which may be substituted, or a saturated orunsaturated, bicyclic or tricyclic fused heterocyclic group which may besubstituted.

[0058] As examples of the saturated or unsaturated, 5- or 6-memberedcyclic hydrocarbon group, may be mentioned cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl and phenyl groups. Cyclopentyl, cyclohexyl andphenyl groups are preferred, with a phenyl group being particularlypreferred.

[0059] The saturated or unsaturated, 5- or 6-membered heterocyclic groupmeans a monovalent heterocyclic group having at least one heteroatomselected from oxygen, sulfur and nitrogen atoms, and examples thereofmay include furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl,pyrazolinyl, oxazolyl, oxazolinyl, thiazolyl, thiazolinyl, thiadiazolyl,furazanyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrrolidinyl,piperazinyl, piperidinyl, oxazinyl, oxadiazinyl, morpholinyl, thiazinyl,thiadiazinyl, thiomorpholinyl, tetrazolyl, triazolyl and triazinylgroups. Pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl,furazanyl, pyridyl, pyrimidyl, pyridazinyl, pyrrolidinyl, piperazinyl,piperidinyl, morpholinyl, thiadiazinyl and triazolyl groups arepreferred, with pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl,pyrrolidinyl, piperazinyl and piperidinyl groups being particularlypreferred. Of these heterocyclic groups, the nitrogen-containingheterocyclic groups may be in the form of an N-oxide.

[0060] The saturated or unsaturated, bicyclic or tricyclic fusedhydrocarbon group means the same saturated or unsaturated, bicyclic ortricyclic fused hydrocarbon group as described in the description of Q⁴in the general formula (1). As specific examples thereof, may bementioned indenyl, indanyl, naphthyl, tetrahydronaphthyl, anthryl andphenanthryl groups, with indenyl, indanyl, naphthyl andtetrahydronaphthyl groups being preferred.

[0061] The saturated or unsaturated, bicyclic or tricyclic fusedheterocyclic group means the same saturated or unsaturated, bicyclic ortricyclic fused heterocyclic group as described in the description of Q⁴in the general formula (1). As specific examples thereof, may bementioned benzofuryl, benzothienyl, indolyl, indolinyl, isoindolyl,indazolyl, quinolyl, tetrahydroquinolyl, isoquinolyl,tetrahydroisoquinolyl, quinazolyl, dihydroquinazolyl,tetrahydroquinazolyl, quinoxalyl, tetrahydroquinoxalyl, cinnolyl,tetrahydrocinnolyl, indolizinyl, tetrahydroindolizinyl, benzothiazolyl,tetrahydrobenzothiazolyl, naphthyridinyl, thienopyridyl,tetrahydrothienopyridyl, thiazolopyridyl, tetrahydrothiazolopyridyl,tetrahydronaphthyridinyl, thiazolopyridazinyl,tetrahydrothiazolopyridazinyl, pyrrolopyridyl, dihydropyrrolopyridyl,tetrahydropyrrolopyridyl, pyrrolopyrimidinyl, dihydropyrrolopyrimidinyl,dihydro-pyridoquinazolyl, pyridopyrimidinyl,tetrahydropyrido-pyrimidinyl, pyranothiazolyl, dihydropyranothiazolyl,furopyridyl, tetrahydrofuropyridyl, oxazolopyridyl,tetrahydrooxazolopyridyl, oxazolopyridazinyl,tetrahydrooxazolopyridazinyl, pyrrolothiazolyl, dihydropyrrolothiazolyl,pyrrolooxazolyl, dihydropyrrolooxazolyl, pyrazolothiazolopyridazinyl,tetrahydropyrazolothiazolopyridazinyl andhexahydrothiazolopyridazinopyridazinyl groups. Preferred arebenzothiazolyl, tetrahydrobenzothiazolyl, thienopyridyl,tetrahydrothienopyridyl, thiazolopyridyl, tetrahydrothiazolopyridyl,thiazolopyridazinyl, tetrahydrothiazolopyridazinyl, pyrrolopyrimidinyl,dihydropyrrolopyrimidinyl, pyranothiazolyl, dihydropyranothiazolyl,furopyridyl, tetrahydrofuropyridyl, oxazolopyridyl,tetrahydrooxazolopyridyl, pyrrolopyridyl, dihydropyrrolopyridyl,tetrahydropyrrolopyridyl, oxazolopyridazinyl,tetrahydrooxazolopyridazinyl, pyrrolothiazolyl, dihydropyrrolothiazolyl,pyrrolooxazolyl, dihydropyrrolooxazolyl,4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl and5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl groups, withtetrahydrobenzothiazolyl, tetrahydrothienopyridyl,tetrahydrothiazolopyridyl, tetrahydrothiazolopyridazinyl,dihydropyrrolopyrimidinyl, dihydropyranothiazolyl,tetrahydrooxazolopyridyl, dihydropyrrolothiazolyl,4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl and5,6-trimethylene-4,5,6,7-tetrahydrothiazolo-pyridazinyl groups beingparticularly preferred. No particular limitation is imposed on thefusing form of the fused heterocyclic groups. For example,thienopyridine may be any of thieno[2,3-b]pyridine,thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, thieno[3,2-c]pyridine,thieno[3,4-b]pyridine and thieno[3,4-c]pyridine, withthieno[2,3-c]pyridine and thieno[3,2-c]pyridine being referred;thiazolopyridine may be any of thiazolo[4,5-b]pyridine,thiazolo[4,5-c]-pyridine, thiazolo[5,4-b]pyridine,thiazolo[5,4-c]-pyridine, thiazolo[3,4-a]pyridine andthiazolo[3,2-a]pyridine, with thiazolo[4,5-c]pyridine andthiazolo[5,4-c]pyridine being preferred; thiazolopyridazine may be anyof thiazolo[4,5-c]pyridazine, thiazolo[4,5-d]-pyridazine,thiazolo[5,4-c]pyridazine and thiazolo[3,2-b]pyridazine, withthiazolo[4,5-d]pyridazine being preferred; pyrrolopyridine may be any ofpyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-b]pyridine,pyrrolo[3,2-c]pyridine, pyrrolo[3,4-d]pyridine andpyrrolo[3,4-c]pyridine, with pyrrolo[2,3-c]pyridine andpyrrolo[3,2-c]pyridine being preferred; pyrrolopyrimidine may be any ofpyrrolo[3,4-d]pyrimidine, pyrrolo[3,2-d]pyrimidine andpyrrolo[2,3-d]pyrimidine, with pyrrolo[3,4-d]pyrimidine being preferred;pyridopyrimidine may be any of pyrido[2,3-d]pyrimidine,pyrido[3,2-d]pyrimidine, pyrido[3,4-d]pyrimidine,pyrido[4,3-d]pyrimidine, pyrido[1,2-c]pyrimidine andpyrido[1,2-a]pyrimidine, with pyrido[3,4-d]pyrimidine andpyrido[4,3-d]pyrimidine being preferred; pyranothiazole may be any ofpyrano[2,3-d]thiazole, pyrano[4,3-d]thiazole, pyrano[3,4-d]thiazole andpyrano[3,2-d]thiazole, with pyrano[4,3-d]thiazole andpyrano[3,4-d]thiazole being preferred; furopyridine may be any offuro[2,3-b]pyridine, furo[2,3-c]pyridine, furo[3,2-b]pyridine,furo[3,2-c]pyridine, furo[3,4-b]-pyridine and furo[3,4-c]pyridine, withfuro[2,3-c]-pyridine and furo[3,2-c]pyridine being preferred;oxazolopyridine may be any of oxazolo[4,5-b]pyridine,oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine,oxazolo[3,4-a]pyridine and oxazolo[3,2-a]pyridine, withoxazolo[4,5-c]pyridine and oxazolo[5,4-c]pyridine being preferred;oxazolopyridazine may be any of oxazolo[4,5-c]pyridazine,oxazolo[4,5-d]pyridazine, oxazolo[5,4-c]pyridazine andoxazolo[3,4-b]pyridazine, with oxazolo[4,5-d]pyridazine being preferred;pyrrolothiazole may be any of pyrrolo[2,1-b]thiazole,pyrrolo[1,2-c]thiazole, pyrrolo[2,3-d]thiazole, pyrrolo[3,2-d]thiazoleand pyrrolo[3,4-d]thiazole, with pyrrolo[3,4-d]thiazole being preferred;and pyrrolooxazole may be any of pyrrolo[2,1-b]oxazole,pyrrolo[1,2-c]oxazole, pyrrolo[2,3-d]oxazole, pyrrolo[3,2-d]oxazole andpyrrolo[3,4-d]oxazole, with pyrrolo[3,4-d]oxazole being preferred.

[0062] Of these heterocyclic groups, the nitrogen-containingheterocyclic groups may be in the form of an N-oxide. Incidentally, theposition of the above substituent group bonded to Q² is not particularlylimited.

[0063] The above-described saturated or unsaturated, 5- or 6-memberedcyclic hydrocarbon groups, saturated or unsaturated, 5- or 6-memberedheterocyclic groups, saturated or unsaturated, bicyclic or tricyclicfused hydrocarbon groups and saturated or unsaturated, bicyclic ortricyclic fused heterocyclic groups may each have 1 to 3 substituents.Examples of the substituents may include a hydroxyl group: halogen atomsof fluorine atom, chlorine atom, bromine atom and iodine atom;halogenomethyl groups having 1 to 3 halogen substituents; an aminogroup; a cyano group; an amidino group; a hydroxyamidino group; linear,branched or cyclic alkyl groups having 1 to 6 carbon atoms (hereinafterreferred to as C₁-C₆ alkyl groups which mean linear, branched and cyclicalkyl groups; for example, linear or branched C₁-C₆ alkyl groups such asmethyl, ethyl, isopropyl and tert-butyl; C₃-C₆ cycloalkyl groups such ascyclopropyl group, cyclobutyl group, cyclopentyl group and1-methylcyclopropyl group; and C₃-C₆ cycloalkyl-C₁-C₆ alkyl groups suchas cyclopropylmethyl group); hydroxy-C₁-C₆ alkyl groups (such ashydroxyethyl and 1,1-dimethyl-2-hydroxyethyl groups); C₁-C₆ alkoxygroups (for example, methoxy group, ethoxy group and the like); C₁-C₆alkoxy-C₁-C₆ alkyl groups; a carboxyl group; C₂-C₆ carboxyalkyl groups(for example, carbocymethyl group and the like) ; C₂-C₆alkoxycarbonyl-C₁-C₆ alkyl groups (for example, methoxycarbonylmethylgroup, tert-butoxycarbonylmethyl group and the like); amidino groupssubstituted by a C₂-C₆ alkoxycarbonyl group; C₂-C₆ alkenyl groups (forexample, vinyl group, allyl group and the like); C₂-C₆ alkynyl groups(for example, ethynyl group, propynyl group and the like); C₂-C₆alkoxycarbonyl groups (for example, methoxycarbonyl group,ethoxycarbonyl group, tert-butoxycarbonyl group and the like); aminoC₁-C₆ alkyl groups (for example, aminomethyl group, aminoethyl group andthe like); C₁-C₆ alkylamino-C₁-C₆ alkyl groups (for example,N-methylaminomethyl group, N-ethylaminomethyl group and the like); C₁-C₆dialkylamino-C₁-C₆ alkyl groups (for example, N,N-dimethylaminomethylgroup, N,N-diethylaminomethyl group and the like); C₂-C₆alkoxycarbonylamino-C₁-C₆ alkyl groups (for example,methoxycarbonylaminoethyl group, tert-butoxycarbonylaminoethyl group andthe like); C₁-C₆ alkanoyl groups (for example, formyl group, acetylgroup, methylpropionyl group, cyclopentanecarbonyl group and the like);C₁-C₆ alkanoylamino-C₁-C₆ alkyl groups (for example, acetylaminomethylgroup and the like); C₁-C₆ alkylsulfonyl groups (for example,methanesulfonyl group and the like); C₁-C₆ alkylsulfonylamino-C₁-C₆alkyl groups (for example, methanesulfonylaminomethyl group and thelike); a carbamoyl group; C₁-C₆ alkylcarbamoyl groups (for example,methylcarbamoyl group, ethylcarbamoyl group, isopropylcarbamoyl group,tert-butylcarbamoyl group and the like); N,N-di(C₁-C₆ alkyl)carbamoylgroups (for example, dimethylcarbamoyl group, diethylcarbamoyl group,methylethylcarbamoyl group and the like); C₁-C₆ alkylamino groups (forexample, N-methylamino group, N-ethylamino group and the like); C₁-C₆dialkylamino groups (for example, N,N-dimethylamino group,N,N-diethylamino group, N-methyl-N-ethylamino group and the like); 5- or6-membered heterocyclic groups containing one of nitrogen, oxygen andsulfur or the same or different two atoms thereof (for example,pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinylgroup, pyridyl group, pyrimidinyl group, tetrahydropyranyl group and thelike); and groups composed of the above 5- or 6-membered heterocyclicgroup and a C₁-C₄ alkyl group (for example, morpholinomethyl group andthe like). As specific examples of Q¹, may be mentioned bicyclicheterocyclic groups such as5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl,4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl,5-cyclopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl,5-carboxymethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl,5-butyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl,5-(4-pyridyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl,5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl,6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl,5-methyl-4,5,6,7-tetrahydroxazolo[5,4-c]pyridin-2-yl,5-methyl-4,6-dihydro-5H-pyrrolo[3,4-d]-thiazol-2-yl,5,7-dihydro-6-methylpyrrolo[3,4-d]-pyrimidin-2-yl,5,6-dimethyl-4,5,6,7-tetrahydro-thiazolo[4,5-d]pyridazin-2-yl,5,6-dimethyl-4,5,6,7-tetrahydroxazolo[4,5-d]pyridazin-2-yl,5-dimethylamino-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl,5-(4-pyridyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl and6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl groups, and a4-(4-pyridyl)phenyl group. Incidentally, Q¹ is not limited by theseexamples at all.

[0064] <On Group Q²>

[0065] The group Q² means a single bond, a linear or branched alkylenegroup having 1 to 6 carbon atoms, a linear or branched alkenylene grouphaving 2 to 6 carbon atoms, a linear or branched alkynylene group having2 to 6 carbon atoms, a group —N(R³)—, in which R³ means a hydrogen atomor alkyl group, a group —N(R⁴)—(CH₂)_(m)—, in which R⁴ means a hydrogenatom or alkyl group, and m is an integer of 1 to 6, a saturated orunsaturated, 5- or 6-membered divalent cyclic hydrocarbon group whichmay be substituted, a saturated or unsaturated, 5- or 6-membereddivalent heterocyclic group which may be substituted, a saturated orunsaturated, divalent bicyclic or tricyclic fused hydrocarbon groupwhich may be substituted, or a saturated or unsaturated, divalentbicyclic or tricyclic fused heterocyclic group which may be substituted.

[0066] In the group Q², as examples of the linear or branched alkylenegroup having 1 to 6 carbon atoms, may be mentioned methylene, ethylene,trimethylene, propylene, tetramethylene, pentamethylene andhexamethylene groups.

[0067] As examples of the linear or branched alkenylene group having 2to 6 carbon atoms, may be mentioned vinylene, propenylene, butenyleneand pentenylene groups. No particular limitation is imposed on theposition of the double bond thereof.

[0068] As examples of the linear or branched alkynylene group having 2to 6 carbon atoms, may be mentioned ethynylene, propynylene, butynylene,pentynylene and hexynylene groups. No particular limitation is imposedon the position of the triple bond thereof.

[0069] R³ in the group —N(R³)— is a hydrogen atom or alkyl group. Thealkyl group means a linear, branched or cyclic alkyl group having 1 to 6carbon atoms, and examples thereof may include methyl, ethyl, isopropyland cyclopropyl groups.

[0070] R⁴ in the group —N(R⁴)—(CH₂)_(m)— is a hydrogen atom or alkylgroup. The alkyl group means a linear, branched or cyclic alkyl grouphaving 1 to 6 carbon atoms, and examples thereof may include methyl,ethyl, isopropyl and cyclopropyl groups. m is an integer of 1 to 6, withan integer of 1 to 3 being preferred.

[0071] The saturated or unsaturated, 5- or 6-membered divalent cyclichydrocarbon group means a divalent group derived from the saturated orunsaturated, 5- or 6-membered cyclic hydrocarbon described in thedescription of Q⁴ in the general formula (1). As specific examplesthereof, may be mentioned cyclohexylene, cyclohexenylene and phenylenegroups, with cyclohexylene and phenylene groups being preferred.

[0072] The saturated or unsaturated, 5- or 6-membered divalentheterocyclic group means a divalent group derived from the saturated orunsaturated, 5- or 6-membered heterocyclic ring described in thedescription of Q⁴ in the general formula (1). As specific examplesthereof, may be mentioned divalent groups derived from furan, pyrrole,thiophene, pyrazole, imidazole, oxazole, oxazolidine, thiazole,thiadiazole, furazane, pyrane, pyridine, pyrimidine, pyridazine,pyrrolidine, piperazine, piperidine, oxazine, oxadiazine, morpholine,thiazine, thiadiazine, thiomorpholine, tetrazole, triazole and triazine.Particularly, divalent groups derived from pyrazole, imidazole, oxazole,thiazole, thiadiazole, furazane, pyridine, pyrimidine, pyridazine,pyrrolidine, piperazine, piperidine, triazole and triazine may bementioned as preferable examples.

[0073] The saturated or unsaturated, divalent bicyclic or tricyclicfused hydrocarbon group means a divalent group derived from thesaturated or unsaturated, bicyclic or tricyclic fused hydrocarbondescribed in the description of Q⁴ in the general formula (1). Asspecific examples thereof, may be mentioned divalent groups derived fromindene, indane, naphthalene, tetrahydronaphthalene, anthracene,phenanthrene and the like. As preferable examples thereof, may bementioned divalent groups derived from indane and naphthalene.

[0074] The saturated or unsaturated, divalent bicyclic or tricyclicfused heterocyclic group means a divalent group derived from thesaturated or unsaturated, bicyclic or tricyclic fused heterocyclic ringdescribed in the description of Q⁴ in the general formula (1). Asspecific examples thereof, may be mentioned divalent groups derived frombenzofuran, benzothiophene, indole, isoindole, indazole, quinoline,tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, quinazoline,dihydroquinazoline, tetrahydroquinazoline, quinoxaline,tetrahydroquinoxaline, cinnoline, tetrahydrocinnoline, indolizine,tetrahydroindolizine, benzothiazole, tetrahydrobenzothiazole,naphthyridine, tetrahydronaphthyridine, thienopyridine,tetrahydrothienopyridine, thiazolopyridine, tetrahydrothiazolopyridine,thiazolopyridazine, tetrahydrothiazolopyridazine, pyrrolopyridine,dihydropyrrolopyridine, tetrahydropyrrolopyridine, pyrrolopyrimidine,dihydropyrrolopyrimidine, dihydropyridoquinazoline, pyranothiazole,dihydropyranothiazole, furopyridine, tetrahydrofuropyridine,oxazolopyridine, tetrahydrooxazolopyridine, oxazolopyridazine,tetrahydrooxazolopyridazine, pyrrolothiazole, dihydropyrrolothiazole,pyrrolooxazole and dihydropyrrolooxazole. As preferable examplesthereof, may be mentioned divalent groups derived from benzofuran,benzothiophene, indole, indazole, quinoline, isoquinoline,tetrahydroisoquinoline, benzothiazole, naphthyridine, thienopyridine,thiazolopyridine, tetrahydrothiazolopyridine, thiazolopyridazine,pyrrolopyridine, tetrahydropyrrolopyridine, pyridopyrimidine,pyranothiazole, dihydropyranothiazole, furopyridine, oxazolopyridine,oxazolopyridazine, pyrrolothiazole, dihydropyrrolothiazole,pyrrolooxazole and dihydropyrrolooxazole. No particular limitation isimposed on the fusing form of the fused heterocyclic group. For example,naphthyridine may be any of 1,5-, 1,6-, 1,7-, 1,8-, 2,6- and2,7-naphthyridine, thienopyridine may be any of thieno[2,3-b]pyridine,thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, thieno[3,2-c]pyridine,thieno[3,4-b]pyridine and thieno[3,4-c]pyridine, thiazolopyridine may beany of thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine,thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine,thiazolo[3,4-a]pyridine and thiazolo[3,2-a]pyridine, thiazolopyridazinemay be any of thiazolo[4,5-c]-pyridazine, thiazolo[4,5-d]pyridazine,thiazolo[5,4-c]-pyridazine and thiazolo[3,2-b]pyridazine,pyrrolopyridine may be any of pyrrolo[2,3-b]pyridine,pyrrolo[2,3-c]pyridine, pyrrolo[3,2-b]pyridine, pyrrolo[3,2-c]pyridine,pyrrolo[3,4-b]pyridine and pyrrolo[3,4-c]pyridine, pyrrolopyrimidine maybe any of pyrrolo[3,4-d]pyrimidine, pyrrolo[3,2-d]pyrimidine andpyrrolo[2,3-d]pyrimidine, pyridopyrimidine may be any of pyrido[2,3-d]pyrimidine, pyrido[3,2-d]pyrimidine and pyrido[3,4-d]pyrimidine,pyranothiazole may be any of pyrano[2,3-d]thiazole,pyrano[4,3-d]thiazole, pyrano[3,4-d]thiazole and pyrano[3,2-d]thiazole,furopyridine may be any of furo[2,3-b]pyridine, furo[2,3-c]pyridine,furo[3,2-b]pyridine, furo[3,2-c]-pyridine, furo[3,4-b]pyridine andfuro[3,4-c]pyridine, oxazolopyridine may be any ofoxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine,oxazolo[5,4-c]pyridine, oxazolo[3,4-a]pyridine andoxazolo[3,2-a]pyridine, oxazolopyridazine may be any ofoxazolo[4,5-c]pyridazine, oxazolo[4,5-d]pyridazine,oxazolo[5,4-c]pyridazine and oxazolo[3,4-b]pyridazine, pyrrolothiazolemay be any of pyrrolo[2,1-b]thiazole, pyrrolo[1,2-c]thiazole,pyrrolo[3,2-d]thiazole and pyrrolo[3,4-d]thiazole, and pyrrolooxazolemay be any of pyrrolo[2,1-b]oxazole, pyrrolo[1,2-c]oxazole,pyrrolo[2,3-d]oxazole, pyrrolo[3,2-d]oxazole and pyrrolo[3,4-d]oxazole.Other fusing forms than these may be allowed.

[0075] The above-described saturated or unsaturated, 5- or 6-membereddivalent cyclic hydrocarbon groups, saturated or unsaturated, 5- or6-membered divalent heterocyclic groups, saturated or unsaturated,divalent bicyclic or tricyclic fused hydrocarbon groups and saturated orunsaturated, divalent bicyclic or.tricyclic fused heterocyclic groupsmay each have 1 to 3 substituents. Examples of the substituents mayinclude a hydroxyl group, halogen atoms of a fluorine, chlorine, bromineand iodine atoms, halogenoalkyl groups having 1 to 3 halogensubstituents, an amino group, a cyano group, aminoalkyl groups, anamidino group, a hydroxyamidino group, linear, branched or cyclic alkylgroups having 1 to 6 carbon atoms (for example, a methyl group, an ethylgroup, etc.), linear, branched or cyclic alkoxy groups having 1 to 6carbon atoms (for example, a methoxy group, an ethoxy group, etc.),amidino group substituted by linear, branched or cyclic alkoxycarbonylgroups having 2 to 7 carbon atoms (for example, a methoxycarbonylamidinogroup, an ethoxycarbonylamidino group, etc.), linear, branched or cyclicalkenyl groups having 2 to 6 carbon atoms (for example, a vinyl group,an allyl group, etc.), linear or branched alkynyl groups having 2 to 6carbon atoms (for example, an ethynyl group, a propynyl group, etc.),linear, branched or cyclic alkoxycarbonyl group having 2 to 6 carbonatoms (for example, a methoxycarbonyl group, an ethoxycarbonyl group,etc.), and a carbamoyl group.

[0076] Preferable groups in Q² described above are a single bond, analkylene group having 1 or 2 carbon atoms, an alkenylene group having 2carbon atoms, an alkynylene group having 2 carbon atoms, group —NH—,group —N(R⁴)—(CH₂)₂—, a saturated or unsaturated, 5- or 6-membereddivalent cyclic hydrocarbon group which may be substituted, a saturatedor unsaturated, 5- or 6-membered divalent heterocyclic group which maybe substituted, and a saturated or unsaturated, divalent bicyclic ortricyclic fused heterocyclic group which may be substituted. Inparticular, a single bond, saturated or unsaturated, divalent 5- or6-membered cyclic hydrocarbon groups such as a cyclohexylene group and aphenylene group, and divalent groups derived from fused heterocyclicrings such as thiazole and piperidine are preferred.

[0077] When Q¹ is a saturated or unsaturated, bicyclic or tricyclicfused hydrocarbon group which may be substituted, or a saturated orunsaturated, bicyclic or tricyclic fused heterocyclic group which may besubstituted, the group Q² is preferably a single bond. The fact that Q²is a single bond means that the general formula (1):

Q¹-Q²-C(═O)—N(R¹)-Q³-N(R²)-T¹-Q⁴   (1)

[0078] wherein R¹, R², Q¹, Q², Q³, Q⁴ and T¹ have the same meanings asdefined above, comes to the following general formula (1′):

Q¹-C(═O)—N(R¹)-Q³-N(R²)-T¹-Q⁴   (1′)

[0079] wherein Q¹ represents the above bicyclic or tricyclic fusedhydrocarbon group or bicyclic or tricyclic fused heterocyclic group, andR¹, R², Q³, Q⁴ and T¹ have the same meanings as defined above.

[0080] Specifically, are preferred those in which the group Q¹ is

[0081] a thienopyridyl group which may be substituted;

[0082] a tetrahydrothienopyridyl group which may be substituted;

[0083] a thiazolopyridyl group which may be substituted;

[0084] a tetrahydrothiazolopyridyl group which may be substituted;

[0085] a thiazolopyridazinyl group which may be substituted;

[0086] a tetrahydrothiazolopyridazinyl group which may be substituted;

[0087] a pyranothiazolyl group which may be substituted;

[0088] a dihydropyranothiazolyl group which may be substituted;

[0089] a furopyridyl group which may be substituted;

[0090] a tetrahydrofuropyridyl group which may be substituted;

[0091] an oxazolopyridyl group which may be substituted;

[0092] a tetrahydrooxazolopyridyl group which may be substituted;

[0093] a pyrrolopyridyl group which may be substituted;

[0094] a dihydropyrrolopyridyl group which may be substituted;

[0095] a tetrahydropyrrolopyridyl group which may be substituted;

[0096] a pyrrolopyrimidinyl group which may be substituted;

[0097] a dihydropyrrolopyrimidinyl group which may be substituted;

[0098] an oxazolopyridazinyl group which may be substituted;

[0099] a tetrahydrooxazolopyridazinyl group which may be substituted;

[0100] a pyrrolothiazolyl group which may be substituted;

[0101] a dihydropyrrolothiazolyl group which may be substituted;

[0102] a pyrrolooxazolyl group which may be substituted;

[0103] a dihydropyrrolooxazolyl group which may be substituted;

[0104] a benzothiazolyl group which may be substituted;

[0105] a tetrahydrobenzothiazolyl group which may be substituted;

[0106] a 4,5,6,7-tetrahydro-5,6-tetramethylenethiazolo-pyridazinyl groupwhich may be substituted; or

[0107] a 5,6-trimethylene-4,5,6,7-tetrahydrothiazolo-pyridazinyl groupwhich may be substituted,

[0108] and Q² is a single bond.

[0109] When Q¹ is a saturated or unsaturated, 5- or 6-membered cyclichydrocarbon group which may be substituted, or a saturated orunsaturated, 5- or 6-membered heterocyclic group which may besubstituted, the group Q² is preferably a saturated or unsaturated, 5-or 6-membered divalent cyclic hydrocarbon group which may besubstituted, or a saturated or unsaturated, 5- or 6-membered divalentheterocyclic group which may be substituted. On group Q¹-Q²,5-(4-pyridyl)thiazolyl group, 1-(4-pyridyl)piperidyl group and the likeare preffered.

[0110] <On Group Q³>

[0111] The group Q³ represents a group:

[0112] in which R⁵, R⁶, R⁷ and R⁸, independently of one another, mean ahydrogen atom, hydroxyl group, halogen atom, halogenoalkyl group, cyanogroup, cyanoalkyl group, acyl group, acylalkyl group, alkyl group,alkenyl group, alkynyl group, alkoxy group, alkoxyalkyl group,hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonylgroup, alkoxycarbonylalkyl group, carbamoyl group, N-alkylcarbamoylgroup, N,N-dialkylcarbamoyl group, carbamoylalkyl group,N-alkylcarbamoylalkyl group, N,N-dialkylcarbamoylalkyl group, arylgroup, aralkyl group, heteroaryl group or heteroarylalkyl group, or thefollowing group:

[0113] in which Q⁵ means a alkylene group having 1 to 8 carbon atoms ora alkenylene group having 2 to 8 carbon atoms, and R⁹ and R¹⁰ are,independently of each other, substituents on a carbon atom of the ringcomprising Q⁵ and mean a hydrogen atom, hydroxyl group, alkyl group,alkenyl group, alkynyl group, halogen atom, halogenoalkyl group, cyanogroup, cyanoalkyl group, amino group, aminoalkyl group,N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group,acylalkyl group, acylamino group which may be substituted, alkoxyiminogroup, hydroxyimino group, acylaminoalkyl group, alkoxy group,alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkylgroup, alkoxycarbonyl group, alkoxycarbonylalkyl group,alkoxycarbonylalkylamino group, carboxyalkylamino group,alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoylgroup, N-alkylcarbamoyl group which may have an substituent on the alkylgroup, N,N-dialkyl-carbamoyl group which may have an substituent on thealkyl group, N-alkenylcarbamoyl group, N-alkenyl-carbamoylalkyl group,N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group,N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group,N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoyl-alkyl group,carbazoyl group which may be substituted by 1 to 3 alkyl groups,alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-memberednitrogen-containing heterocyclic carbonyl group which may besubstituted, carbamoylalkyl group, N-alkylcarbamoylalkyl group which mayhave an substituent on the alkyl group, N,N-dialkylcarbamoylalkyl groupwhich may have an substituent on the alkyl group, carbamoyloxyalkylgroup, N-alkylcarbamoyloxyalkyl group, N,N-dialkylcarbamoyloxyalkylgroup, 3- to 6-membered nitrogen-containing heterocyclic carbonylalkylgroup which may be substituted, 3- to 6-membered nitrogen-containingheterocyclic carbonyloxyalkyl group which may be substituted, arylgroup, aralkyl group, heteroaryl group, heteroarylalkyl group,alkylsulfonylamino group, arylsulfonylamino group,alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl group,alkylsulfonylaminocarbonyl group, arylsulfonylaminocarbonyl group,alkylsulfonylaminocarbonylalkyl group, arylsulfonylaminocarbonylalkylgroup, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxygroup, acyloxy group or acyloxyalkyl group, or R⁹ and R¹⁰, together witheach other, denote an alkylene group having 1 to 5 carbon atoms,alkenylene group having 2 to 5 carbon atoms, alkylenedioxy group having1 to 5 carbon atoms or carbonyldioxy group.

[0114] The substituents R⁵, R⁶, R⁷ and R⁸ will be described in detail.The halogen atom means a fluorine, chlorine, bromine or iodine atom.Examples of the alkyl group include linear, branched or cyclic C₁-C₆alkyl groups (for example, a methyl group, a cyclopropyl group, anisobutyl group and the like). Examples of the halogenoalkyl groupinclude the 1 to 3 halogen-substituted alkyl groups (for example, achloromethyl group, an 1-bromoethyl group, a trifluoromethyl group andthe like). Examples of the cyanoalkyl group include the C₁-C₆ alkylgroups substituted with a cyano group (for example, a cyanomethyl group,a 1-cyanoethyl group and the like). Examples of the alkenyl groupinclude linear or branched alkenyl groups having 2 to 6 carbon atoms anda double bond (for example, a vinyl group, an allyl group and the like).Examples of the alkynyl group include linear or branched alkynyl groupshaving 2 to 6 carbon atoms and a triple bond (for example, an ethynylgroup, a propynyl group and the like) Examples of the acyl group includeC₁-C₆ alkanoyl groups (for example, a formyl group, an acetyl group andthe like), C₇-C₁₅ aroyl groups such as a benzoyl group and a naphthoylgroup, and arylalkanoyl groups that are the C₁-C₆ alkanoyl groupssubstituted with the C₆-C₁₄ aryl group (for example, a phenacetyl groupand the like). Examples of the acylalkyl group include the C₁-C₆ alkylgroups substituted with the acyl group (for example, an acethylmethylgroup and the like). Examples of the alkoxy group include linear,branched or cyclic C₁-C₆ alkoxy groups (for example, a methoxy group, acyclopropoxy group, an isopropoxy group and the like). Examples of thealkoxyalkyl group include the C₁-C₆ alkyl groups substituted with theC₁-C₆ alkoxy group (for example, a methoxymethyl group, an ethoxymethylgroup and the like). Examples of the hydroxyalkyl group include theC₁-C₆ alkyl groups substituted with a hydroxyl group (for example, ahydroxymethyl group, a 1-hydroxyethyl group and the like). Examples ofthe carboxyalkyl group include the C₁-C₆ alkyl groups substituted with acarboxyl group (for example, a carboxymethyl group, a 1-carboxyethylgroup and the like). Examples of the alkoxycarbonyl group include groupscomposed of the C₁-C₆ alkoxy group and a carbonyl group (for example, amethoxycarbonyl group, an ethoxycarbonyl group and the like). Examplesof the alkoxycarbonylalkyl group include the C₁-C₆ alkyl groupssubstituted with the C₁-C₆ alkoxycarbonyl group (for example, amethoxycarbonylethyl group, an ethoxycarbonylethyl group and the like).Examples of the carbamoylalkyl group include the C₁-C₆ alkyl groupssubstituted a carbamoyl group (for example, a carbamoyl methyl group, acarbamoylethyl group and the like), Examples of the N-alkylcarbamoylgroup include carbamoyl groups substituted with the C₁-C₆ alkyl group(for example, an N-methylcarbamoyl group, an N-isopropylcarbamoyl group,N-cyclopropylcarbamoyl group and the like). Examples of theN,N-dialkylcarbamoyl group include carbamoyl groups substituted with thetwo C₁-C₆ alkyl groups which are the same or different from each other(for example, an N,N-dimethylcarbamoyl group, anN-ethyl-N-methylcarbamoyl group and the like). The examples of theN-alkylcarbamoylalkyl group include the C₁-C₆alkyl groups substitutedwith the N-alkylcarbamoyl group (for example, an N-methylcarbamoylmethylgroup, an N-methylcarbamoylethyl group and the like). Examples of theN,N-dialkylcarbamoylalkyl group include the C₁-C₆ alkyl groupssubstituted with the N,N-dialkylcarbamoyl group (for example, anN,N-dimethylcarbamoylmethyl group, an N,N-dimethylcarbamoylethyl groupand the like). Examples of the heteroaryl group include the sameheteroaryl groups as described in the description of Q⁴ in the generalformula (1). Examples of the heteroarylalkyl group include the C₁-C₆alkyl groups substituted with the heteroaryl group (for example, athienylmethyl group,a pyridylethyl group and the like). Examples of thearyl group include aryl groups having 6 to 14 carbon atoms, such as aphenyl group and a naphthyl group. The aryl groups may have 1 to 3substituents selected from the C₁-C₆ alkyl groups, the C₁-C₆ alkanoylgroups, a hydroxyl group, a nitro group, a cyano group, halogen atoms,the C₂-C₆ alkenyl groups, the C₂-C₆ alkynyl groups, the halogenoalkylgroups, the alkoxy groups, a carboxy group, a carbamoyl group, thealkoxycarbonyl groups and the like. Examples of the aralkyl groupinclude C₁-C₆ alkyl groups substituted with the C₆-C₁₄ aryl groups (forexample, a benzyl group, a phenetyl group and the like). Incidentally,in the above description, no particular limitation is imposed on thesubstituting position.

[0115] The following group will now be described in detail.

[0116] wherein Q⁵, R⁹ and R¹⁰ have the same meaning as defined above,and numerals 1 and 2 indicate positions.

[0117] A portion of the cyclic structure having the group Q⁵ is a 3- to10-membered divalent cyclic hydrocarbon group which may have a doublebond, preferably a 3- to 8-membered divalent cyclic hydrocarbon group,more preferably a 5- to 7-membered divalent cyclic hydrocarbon group.Among others, a group in which Q⁵ is an alkylene group is preferred.This cyclic hydrocarbon group may have both cis and trans structures inthe relation between position 1 and position 2. However, the trans-formis preferred in the case of the 5-membered ring, while both cis-form andtrans-form are preferred in the 6- or 7-membered ring.

[0118] The substituents R⁹ and R¹⁰ will now be described in detail.

[0119] The alkyl group, alkenyl group, alkynyl group, halogen atom,halogenoalkyl group, cyanoalkyl group, acyl group, acylalkyl group,alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyalkyl group,alkoxycarbonyl group, alkoxycarbonylalkyl group, aryl group, aralkylgroup, heteroaryl group and heteroarylalkyl group are the same as thosedescribed above in the description as to R⁵, R⁶, R⁷ and R⁸. Examples ofthe acylamino group which may be substituted include the amino groupssubstituted with the acyl group (for example, a formylamino group, anacetylamino group and the like) and besides acyl groups having 1 toseveral substituents selected from halogen atoms, a hydroxyl group,C₁-C₆ alkoxy groups, a amino group, N—C₁-C₆ alkylamino groups,N,N-di-C₁-C₆ alkylamino groups, a carboxyl group, C₂-C₆ alkoxycarbonylgroups and the like (for example, a 2-methoxyacetylamino group, a3-aminopropionylamino group and the like). Examples of theacylaminoalkyl group include the C₁-C₆ alkyl groups substituted with theacylamino group (for example, a formylaminomethyl group, anacetylaminomethyl group and the like). Examples of the aminoalkyl groupinclude the C₁-C₆ alkyl groups substituted with an amino group (forexample, an aminomethyl group, a 1-aminoethyl group and the like).Examples of the N-alkylaminoalkyl group include the amino-C₁-C₆alkylgroups substituted with the C₁-C₆ alkyl group on the nitrogen atom (forexample, an N-methylaminomethyl group, an N-methylaminoethyl group andthe like). Examples of N,N-dialkylaminoalkyl group include theamino-C₁-C₆ alkyl groups respectively substituted with two C₁-C₆alkylgroups on the nitrogen atoms (for example, an N,N-dimethylaminomethylgroup, an N-ethyl-N-methylaminoethyl group and the like). Examples ofthe N-alkenylcarbamoyl group include carbamoyl groups substituted with alinear or branched C₂-C₆ alkenyl group (for example, an allylcarbamoylgroup and the like). Examples of the N-alkenylcarbamoylalkyl groupinclude C₁-C₆ alkyl groups substituted with the N-alkenylcarbamoyl group(for example, an allylcarbamoylethyl group and the like). Examples ofthe N-alkenyl-N-alkylcarbamoyl group include the N-alkenylcarbamoylgroups substituted with a linear or branched C₁-C₆ alkyl group on thenitrogen atom (for example, an N-allyl-N-methylcarbamoyl group and thelike). Example of the N-alkenyl-N-alkylcarbamoylalkyl group include theN-alkenylcarbamoylalkyl groups substituted with a linear or branchedC₁-C₆ alkyl group on the nitrogen atom (for example,N-allyl-N-methylcarbamoylmethyl group and the like). Example of theN-alkoxycarbamoyl group include carbamoyl groups substituted with alinear or branched C₁-C₆ alkoxy group (for example, a methoxycarbamoylgroup and the like). Examples of the N-alkoxycarbamoylalkyl groupinclude linear or branched C₁-C₆ alkyl groups substituted with theN-alkoxycarbamoyl group (for example, a methoxycarbamoylmethyl group andthe like). Examples of the N-alkyl-N-alkoxycarbamoyl group includecarbamoyl groups substituted with linear or branched C₁-C₆ alkoxy groupand C₁-C₆ alkyl group (for example, N-ethyl-N-methoxycarbamoyl group andthe like). Examples of the N-alkyl-N-alkoxycarbomoylalkyl group includelinear or branched C₁-C₆ alkyl groups substituted with theN-alkyl-N-alkoxycarbamoyl group (for example, anN-ethyl-N-methoxycarbamoylmethyl group and the like). Examples of thecarbazoyl group which may be substituted by 1 to 3 alkyl groups includea carbazoyl group, and besides carbazoyl groups substituted with 1 to 3linear or branched C₁-C₆ alkyl groups (for example, a 1-methylcarbazoylgroup, a 1,2-dimethylcarbazoyl group and the like). Examples of thealkylsulfonyl group include linear or branched C₁-C₆ alkylsulfonylgroups (for example, a methanesulfonyl group and the like). Examples ofthe alkylsulfonylalkyl group include linear or branched C₁-C₆ alkylgroups substituted with the alkylsulfonyl group (for example, amethanesulfonylmethyl group and the like) Examples of the alkoxyiminogroup include C₁-C₆ alkoxyimino groups (for example, a methoxyiminogroup, an ethoxyimino group and the like). Examples of thealkoxycarbonylalkylamino group include amino groups substituted with thealkoxycarbonylalkyl group (for example, a methoxycarbonylmethylaminogroup, an ethoxycarbonylpropylamino group and the like). Examples of thecarboxyalkylamino group include amino groups substituted with thecarboxyalkyl group (for example, a carboxymethylamino group, acarboxyethylamino group and the like). Examples of thealkoxycarbonylamino group include amino groups substituted with thealkoxycarbonyl group (for example, a methoxycarbonylamino group, atert-butoxycarbonylamino group and the like). Examples of thealkoxycarbonylaminoalkyl group include the alkyl groups substituted withthe alkoxycarbonylamino group (for example, a methoxycarbonylaminomethylgroup, a tert-butoxycarbonylaminoethyl group and the like). TheN-alkylcarbamoyl group which may have a substituent on the alkyl groupmeans a carbamoyl group substituted by a linear, branched or cyclicC₁-C₆ alkyl group which may be substituted by a hydroxyl group, aminogroup, N—C₁-C₆ alkylamino group, amidino group, halogen atom, carboxylgroup, cyano group, carbamoyl group, C₁-C₆ alkoxy group, C₁-C₆ alkanoylgroup, C₁-C₆ alkanoylamino group, C₁-C₆ alkyl-sulfonylamino group or thelike, and examples thereof include N-methylcarbamoyl group,N-ethylcarbamoyl group, N-isopropylcarbamoyl group,N-cyclopropylcarbamoyl group, N-(2-hydroxyethyl)carbamoyl group,N-(2-fluoroethyl)-carbamoyl group, N-(2-cyanoethyl)carbamoyl group,N-(2-methoxyethyl)carbamoyl group, N-carboxymethylcarbamoyl group,N-(2-aminoethyl)carbamoyl group, N-(2-amidino-ethyl)carbamoyl group andthe like. Examples of the N,N-dialkylcarbamoyl group which may have asubstituent on the alkyl group means a carbamoyl group substituted by 2linear, branched or cyclic C₁-C₆ alkyl groups which may be substitutedby a hydroxyl group, amino group, N—C₁-C₆ alkylamino group, amidinogroup, halogen atom, carboxyl group, cyano group, carbamoyl group, C₁-C₆alkoxy group, C₁-C₆ alkanoyl group, C₁-C₆ alkanoylamino group, C₁-C₆alkylsulfonylamino group or the like, and examples thereof includeN,N-dimethylcarbamoyl group, N,N-diethylcarbamoyl group,N-ethyl-N-methylcarbamoyl group, N-isopropyl-N-methylcarbamoyl group,N-(2-hydroxyethyl)-N-methylcarbamoyl group,N,N-bis(2-hydroxyethyl)-carbamoyl group, N,N-bis(2-fluoroethyl)carbamoylgroup, N-(2-cyanoethyl)-N-methylcarbamoyl group,N-(2-methoxy-ethyl)-N-methylcarbamoyl group,N-carboxymethyl-N-methylcarbamoyl group, N,N-bis(2-aminoethyl)carbamoylgroup and the like. N-alkylcarbamoylalkyl group which may have asubstituent on the alkyl group include linear or branched C₁-C₆ alkylgroup substituted with the N-alkylcarbamoyl group which may have asubstituent on the alkyl group (for example, N-methylcarbamoylmethylgroup, N-(2-hydroxyethyl)-carbamoylmethyl group and the like). Examplesof the N,N-dialkylcarbamoylalkyl group which may have a substituent onthe alkyl group include linear or branched C₁-C₆ alkyl groupssubstituted with the N,N-dialkylcarbamoyl group which may have asubstituent on the alkyl group (for example, anN,N-dimethylcarbamoylmethyl group, anN-(2-hydroxyethyl)-N-methylmethylcarbamoylmethyl group and the like).

[0120] The 3- to 6-membered nitrogen-containing heterocyclic carbonylgroup which may be substituted is a group composed of a saturated orunsaturated, nitrogen-containing heterocyclic ring and a carbonyl group.The nitrogen-containing heterocyclic ring means a 3- to 6-memberedheterocyclic ring which at least containing 1 to 3 nitrogen atoms andmay further contain an oxygen atom or sulfur atom. The heterocyclic ringmay have a substituent such as a hydroxy group, halogen atom, aminogroup or C₁-C₆ alkyl group. As specific examples thereof, may bementioned an azlidinylcarbonyl group, azetidinylcarbonyl group,3-hydroxyazetidinylcarbonyl group, 3-methoxyazetidinylcarbonyl group,pyrrolidinylcarbonyl group, 3-hydroxypyrrolidinylcarbonyl group,3-fluoropyrrolidinylcarbonyl group, piperidinylcarbonyl group,piperazinylcarbonyl group and morpholinylcarbonyl group.

[0121] Examples of the 3- to 6-membered nitrogen-containing heterocycliccarbonylalkyl group which may be substituted include the C₁-C₆ alkylgroups substituted with the 3- to 6-membered nitrogen-containingheterocyclic carbonyl group which may have be substituted (for example,an azetidinyl-carbonylmethyl group, a pyrrolidinylcarbonylethyl groupand the like).

[0122] Examples of the 3- to 6-membered nitrogen-containing heterocycliccarbonyloxyalkyl group which may be substituted include the C₁-C₆ alkylgroups substituted with the 3- to 6-membered nitrogen-containingheterocyclic carbonyloxy group which is composed of the 3- to 6-memberednitrogen-containing heterocyclic carbonyl group which may be substitutedand an oxygen atom (for example, a piperidinylcarbonyloxyethyl group,morpholinyl-carbonyloxymethyl group and the like).

[0123] Example of the carbamoylalkyl group include the C₁-C₆ alkylgroups substituted with a carbamoyl group (for example, acarbamoylmethyl group, a carbamoylethyl group and the like).

[0124] Examples of the carbamoyloxyalkyl group include the C₁-C₆ alkylgroups substituted with a carbamoyloxy group which is composed of acarbamoyl group and an oxygen atom (for example, a carbamoyloxymethylgroup, a carbamoyloxyethyl group and the like).

[0125] Examples of the N-alkylcarbamoyloxyalkyl group include the C₁-C₆alkyl groups substituted with the N-alkylcarbamoyloxy group which iscomposed of the N-alkylcarbamoyl group, which may have a substituent onthe alkyl group, and an oxygen atom (for example, anN-methylcarbamoyloxymethyl group, an N-methylcarbamoyl-oxyethyl groupand the like).

[0126] Examples of the N,N-dialkylcarbamoyloxyalkyl group include theC₁-C₆ alkyl groups substituted with the N,N-dialkylcarbamoyloxy groupwhich is composed of the N,N-dialkylcarbamoyl group, which may have asubstituent on the alkyl group, and an oxygen atom (for example, anN,N-dimethylcarbamoyloxymethyl group, anN-ethyl-N-methylcarbamoyloxyethyl group and the like).

[0127] Examples of the alkylsulfonylamino group include amino groupssubstituted with an alkylsulfonyl group having the C₁-C₆ alkyl group(for example, a methylsulfonylamino group, an isopropylsulfonylaminogroup and the like).

[0128] Examples of the arylsulfonylamino group include amino groupssubstituted with an arylsulfonyl group having the aryl group (forexample, a phenylsulfonylamino group, a naphthylsulfonylamino group andthe like).

[0129] Examples of the alkylsulfonylaminoalkyl group include the C₁-C₆alkyl groups substituted with the C₁-C₆ alkylsulfonylamino group (forexample, a methylsulfonylaminomethyl group, a methylsulfonylaminoethylgroup and the like).

[0130] Examples of the arylsulfonylaminoalkyl group include the C₁-C₆alkyl groups substituted with the arylsulfonylamino group (for example,a phenylsulfonylaminomethyl group, a naphthylsulfonylaminoethyl groupand the like).

[0131] Examples of the alkylsulfonylaminocarbonyl group include groupscomposed of the C₁-C₆ alkylsulfonylamino group and a carbonyl group (forexample, a methylsulfonylaminocarbonyl group, anisopropylsulfonylaminocarbonyl group and the like).

[0132] Examples of the arylsulfonylaminocarbonyl group include groupscomposed of the arylsulfonylamino group and a carbonyl group (forexample, a phenylsulfonylaminocarbonyl group, anaphthylsulfonylaminocarbonyl group and the like).

[0133] Examples of the alkylsulfonylaminocarbonylalkyl group include theC₁-C₆ alkyl groups substituted with the C₁-C₆ alkylsulfonylaminocarbonylgroup (for example, a methylsulfonylaminocarbonylmethyl group, anisopropylsulfonylaminocarbonylmethyl group and the like)

[0134] Examples of the arylsulfonylaminocarbonylalkyl group include. theC₁-C₆ alkyl groups substituted with the arylsulfonylaminocarbonyl group(for example, a phenylsulfonylaminocarbonylmethyl group, anaphthylsulfonylaminocarbonylmethyl group and the like).

[0135] The acyloxy group means a group composed of the acyl group and anoxygen atom (for example, a formyloxy group, an acetyloxy group and thelike).

[0136] Examples of the acyloxyalkyl group include the C₁-C₆ alkyl groupssubstituted with the acyloxy group (for example, a formyloxymethylgroup, an acetyloxymethyl group and the like).

[0137] Examples of the aralkyloxy group include the alkoxy groupssubstituted with the aryl group (for example, a benzyloxy group, anaphthylmethoxy group and the like).

[0138] Examples of the carboxyalkyloxy group include the alkoxy groupssubstituted with a carboxyl group (for example, a carboxymethoxy group,a carboxyethoxy group and the like).

[0139] The alkylene group means a linear or branched alkylene grouphaving 1 to 5 carbon atoms, and examples thereof include a methylenegroup, an ethylene group, a propylene group and the like.

[0140] The alkenylene group is an alkenylene group having 2 to 5 carbonatoms and a double bond, and examples thereof include a vinylene group,a propenylene group and the like. Examples of the alkylenedioxy groupinclude those having 1 to 5 carbon atoms, such as a methylenedioxygroup, an ethylenedioxy group and a propylenedioxy group.

[0141] The carbonyldioxy group is a group represented by —O—C(═O)—O—.Incidentally, no particular limitation is imposed on the substitutingposition in the above description.

[0142] Among these substituents represented by R⁹ and R¹⁰, the hydrogenatom, hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogenatom, halogenoalkyl group, amino group, hydroxyimino group, alkoxyiminogroup, aminoalkyl group, N-alkylaminoalkyl group, N,N-dialkylaminoalkylgroup, acyl group, acylalkyl group, acylamino group which may besubstituted, acylaminoalkyl group, alkoxy group, alkoxyalkyl group,hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonylgroup, alkoxycarbonylalkyl group, alkoxycarbonylamino group,alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl groupwhich may have a substituent on the alkyl group, N,N-dialkylcarbamoylgroup which may have a substituent on the alkyl groups,N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group,N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group,N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group,N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group,carbazoyl group which may be substituted by 1 to 3 alkyl groups,alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-memberednitrogen-containing heterocyclic carbonyl group which may besubstituted, 3- to 6-membered nitrogen-containing heterocycliccarbonyloxyalkyl group which may be substituted, carbamoylalkyl group,carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group,N,N-dialkylcarbamoyloxyalkyl group, N-alkylcarbamoylalkyl group whichmay have a substituent on the alkyl group, N,N-dialkylcarbamoylalkylgroup which may have a substituent on the alkyl groups,alkylsulfonylamino group, alkylsulfonylaminoalkyl group, oxo group,acyloxy group, and acyloxyalkyl group are preferred. The alkylene group,alkenylene group, alkylenedioxy group and carbonyldioxy group which areformed by R⁹ and R¹⁰ together with each other are also preferred.

[0143] It is preferred that R⁹ be a hydrogen atom, and R¹⁰ is one of thesubstituents mentioned above as preferable groups. In this case,examples of a group more preferred as R¹⁰ include the hydrogen atom,hydroxyl group, alkyl group, halogen atom, hydroxyimino group,N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group,acylamino group which may be substituted, acylaminoalkyl group, alkoxygroup, alkoxyalkyl group, hydroxyalkyl group, carboxyl group,alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylaminogroup, carbamoyl group, N-alkylcarbamoyl group which may have asubstituent on the alkyl group, N,N-dialkylcarbamoyl group which mayhave a substituent on the alkyl groups, N-alkenylcarbamoyl group,N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group,N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group,N-alkyl-N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoylalkyl group,carbazoyl group which may be substituted by 1 to 3 alkyl groups,alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-memberednitrogen-containing heterocyclic carbonyl group which may besubstituted, 3- to 6-membered nitrogen-containing heterocycliccarbonyloxyalkyl group which may be substituted, carbamoylalkyl group,N,N-dialkylcarbamoyloxyalkyl group, N-alkylcarbamoylalkyl group whichmay have a substituent on the alkyl group, N,N-dialkylcarbamoylalkylgroup which may have a substituent on the alkyl groups,alkylsulfonylamino group, alkylsulfonylaminoalkyl group, and acyloxygroup.

[0144] Of these, as examples of R¹⁰, are particularly preferred thehydrogen atom, hydroxyl group, alkyl group, N,N-dialkylaminoalkyl group,acylamino group which may be substituted, acylaminoalkyl group, alkoxygroup, alkoxyalkyl group, hydroxyalkyl group, alkoxycarbonyl group,alkoxycarbonylamino group, carbamoyl group, N-alkylcarbamoyl group whichmay have a substituent on the alkyl group, N,N-dialkylcarbamoyl groupwhich may have a substituent on the alkyl groups, N-alkenylcarbamoylgroup, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group,N-alkenyl-N-alkylcarbamoylalkyl group, N-alkyl-N-alkoxycarbamoyl group,carbazoyl group which may be substituted by 1 to 3 alkyl groups,alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-memberednitrogen-containing heterocyclic carbonyl group which may besubstituted, N,N-dialkylcarbamoyloxyalkyl group, N-alkylcarbamoylalkylgroup which may have a substituent on the alkyl group,N,N-dialkylcarbamoylalkyl group which may have a substituent on thealkyl groups, alkylsulfonylamino group, alkylsulfonylaminoalkyl group,and acyloxy group.

[0145] As specific preferable examples of R⁹ and R¹⁰, may be mentioned ahydrogen atom, hydroxyl group, methyl group, ethyl group, isopropylgroup, N,N-dimethylaminomethyl group, N,N-dimethylaminoethyl group,N,N-diethylaminomethyl group, acetylamino group, methoxyacetylaminogroup, acetylaminomethyl group, acetylaminoethyl group, methoxy group,ethoxy group, methoxymethyl group, methoxyethyl group, hydroxymethylgroup, 2-hydroxyethyl group, 1-hydroxy-1-methylethyl group,methoxycarbonyl group, ethoxycarbonyl group, methoxycarbonylamino group,ethoxycarbonylamino group, N-allylcarbamoyl group,N-allylcarbamoylmethyl group, N-allyl-N-methylcarbamoyl group,N-allyl-N-methylcarbamoylmethyl group, N-methoxy-N-methylcarbamoylgroup, N,N-dimethylcarbazoyl group, N,N,N′-trimethylcarbazoyl group,methanesulfonyl group, methanesulfonylmethyl group, ethanesulfonylmethylgroup, N-methylcarbamoyl group, N-ethylcarbamoyl group,N-propylcarbamoyl group, N-isopropylcarbamoyl group,N-tert-butylcarbamoyl group, N-cyclopropylcarbamoyl group,N-cyclopropylmethylcarbamoyl group,N-(1-ethoxycarbonylcyclopropyl)carbamoyl group,N-(2-hydroxyethyl)carbamoyl group, N-(2-fluoroethyl)-carbamoyl group,N-(2-methoxyethyl)carbamoyl group, N-(carboxymethyl)carbamoyl group,N-(2-aminoethyl)-carbamoyl group, N-(2-amidinoethyl)carbamoyl group,N,N-dimethylcarbamoyl group, N,N-diethylcarbamoyl group,N-ethyl-N-methylcarbamoyl group, N-isopropyl-N-methyl-carbamoyl group,N-methyl-N-propylcarbamoyl group, N-(2-hydroxyethyl)-N-methylcarbamoylgroup, N-(2-fluoroethyl)-N-methylcarbamoyl group,N,N-bis(2-hydroxyethyl)carbamoyl group, N,N-bis(2-fluoroethyl)carbamoylgroup, N-(2-methoxyethyl)-N-methylcarbamoyl group,N-carboxymethyl-N-methylcarbamoyl group, N,N-bis(2-aminoethyl)carbamoylgroup, azetidinocarbonyl group, 3-methoxyazetidinocarbonyl group,3-hydroxyazetidinocarbonyl group, pyrrolidinocarbonyl group,3-hydroxypyrrolidinocarbonyl group, 3-fluoropyrrolidinocarbonyl group,3,4-dimethoxypyrrolidinocarbonyl group, piperidinocarbonyl group,piperazinocarbonyl group, morpholinocarbonyl group,N-methylcarbamoylmethyl group, N-methylcarbamoylethyl group,N-ethylcarbamoyl-methyl group, N-(2-fluoroethyl)carbamoylmethyl group,N-(2-methoxyethyl)carbamoylmethyl group, N,N-dimethylcarbamoylmethylgroup, N,N-dimethylcarbamoyl-ethyl group,N-(2-fluoroethyl)-N-methylcarbamoylmethyl group,N-(2-methoxyethyl)-N-methylcarbamoylmethyl group,N,N-dimethylcarbamoyloxymethyl group,2-(N-ethyl-N-methylcarbamoyloxy)ethyl group, methylsulfonylamino group,ethylsulfonylamino group, methylsulfonylaminomethyl group andmethylsulfonylaminoethyl group. As described above, it is preferred thatR⁹ be a hydrogen atom, and R¹⁰ is one of these specified substituents.However, R⁹ and R¹⁰ are not limited to these specific substituents atall.

[0146] The group T¹ is a carbonyl group or sulfonyl group, and ispreferably a carbonyl group when the group Q¹ is a bicyclic or tricyclicfused hydrocarbon group, or bicyclic or tricyclic fused heterocyclicgroup, and the group Q² is a single bond.

[0147] R¹ and R² are, independently of each other, a hydrogen atom,hydroxyl group, alkyl group or alkoxy group, preferably a hydrogen atomor alkyl group, more preferably a hydrogen atom.

[0148] Stereoisomers or optical isomers derived from an asymmetriccarbon atom may be present in the compounds of the present inventionrepresented by the general formula (1). However, these stereoisomers,optical isomers and mixtures thereof are all included in the presentinvention.

[0149] No particular limitation is imposed on salts of the compounds ofthe present invention represented by the general formula (1) so far asthey are pharmaceutically acceptable salts. However, specific examplesthereof include mineral acid salts such as hydrochlorides,hydrobromides, hydriodides, phosphates, nitrates and sulfates;benzoates; organic sulfonates such as methanesulfonates,2-hydroxyethanesulfonates and p-toluenesulfonates; and organiccarboxylates such as acetates, propanoates, oxalates, malonates,succinates, glutarates, adipates, tartrates, maleates, malates andmandelates. In the case where the compounds represented by the generalformula (1) have an acidic group, they may be salts of alkali metal ionsor alkaline earth metal ions. No particular limitation is imposed on thesolvates thereof so far as they are pharmaceutically acceptablesolvates. As specific examples thereof, however, may be mentionedhydrates and solvates with ethanol. When a nitrogen atom is present inthe general formula (1), such a compound may be converted to an N-oxidethereof.

[0150] The preparation process of the ethylenediamine derivatives (1)according to the present invention will hereinafter be described.

[0151] [Preparation Process 1]

[0152] An ethylenediamine derivative represented by the general formula(1), a salt thereof, a solvate thereof, or an N-oxide thereof can beprepared in accordance with, for example, the following process:

[0153] wherein Q¹, Q², Q³, Q⁴, R¹ and R² have the same meanings asdefined above, and T¹ represents a carbonyl group.

[0154] A mixed acid anhydride, acid halide, activated ester or the like,which is derived from carboxylic acid (3), may react with diamine (2),giving compound (4). The resultant compound (4) may react withcarboxylic acid (5) under the same conditions, giving compound (1)according to the present invention can be prepared. In the abovereaction steps, reagents and conditions, which are generally used inpeptide synthesis, may be applied. The mixed acid anhydride can beprepared by, for example, reaction of a chloroformate such as ethylchloroformate or isobutyl chloroformate with carboxylic acid (3) in thepresence of a base. The acid halide can be prepared by treatingcarboxylic acid (3) with an acid halide such as thionyl chloride oroxalyl chloride. The activated ester includes various kinds of esters.Such an ester can be prepared by, for example, reaction of a phenol suchas p-nitrophenol, N-hydroxybenzotriazol, or N-hydroxysccinimide withcarboxylic acid (3) using a condensing agent such asN,N′-dicyclohexylcarbodiimide orN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride. Theactivated ester can also be prepared by reaction of carboxylic acid (3)with pentafluorophenyl trifluoroacetate or the like, reaction ofcarboxylic acid (3) with 1-benzotriazolyloxy-tripyrrolidinophosphoniumhexafluorophosphite, reaction of carboxylic acid (3) with diethylcyanophosphonate (Shioiri method), reaction of carboxylic acid (3) withtriphenylphosphine and 2,2′-dipyridyl disulfide (Mukaiyama method) orthe like. The thus-obtained mixed acid anhydride, acid halide oractivated ester of carboxylic acid (3) may react with diamine (2) at−78° C. to 150° C. in the presence of a proper base in an inert solvent,giving compound (4). Thus-obtained compound (4) may react with a mixedacid anhydride, acid halide or activated ester of carboxylic acid (5)under the same conditions, giving compound (1) according to the presentinvention. The reagents and reaction conditions in the reaction ofcompound (4) with carboxylic acid (5) are the same as those in thereaction of diamine (2) with carboxylic acid (3).

[0155] As specific examples of the base used in each step, may bementioned carbonates of alkali metals or alkaline earth metals, such assodium carbonate and potassium carbonate, alkali metal alkoxides such assodium ethoxide and potassium butoxide, alkali metal hydroxides such assodium hydroxide and potassium hydroxide, and hydrides of alkali metalsor alkaline earth metals, such as sodium hydride and potassium hydride;organic metal bases exemplified by alkyllithium such as n-butyllithium,and dialkylaminolithium such as lithium diisopropylamide; organic metalbases exemplified by bis(silyl)amine, such aslithium-bis(trimethylsilyl)-amide; and organic bases such as pyridine,2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,N-methylmorpholine, diisopropylethylamine anddiazabicyclo[5.4.0]undec-7-ene (DBU).

[0156] Examples of the inert solvent used in this reaction include alkylhalide type solvents such as dichloromethane, chloroform and carbontetrachloride, etheric solvents such as tetrahydrofuran,1,2-dimethoxyethane and dioxane, aromatic solvents such as benzene andtoluene, amide solvents such as N,N-dimethylformamide,N,N-dimethylacetamide and N-methylpyrrolidin-2-one. In addition to thesesolvent, a sulfoxide solvent such as dimethyl sulfoxide or sulfolane, aketone solvent such as acetone or methyl ethyl ketone, or the like maybe used in some cases.

[0157] [Preparation Process 2]

[0158] Compound (1) according to the present invention can also beprepared in accordance with the following process:

[0159] wherein Q¹, Q², Q³, Q⁴, R¹ and R² have the same meanings asdefined above, T¹ represents a carbonyl group, Boc represents atert-butoxycarbonyl group, and Boc-ON represents a2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile.

[0160] As described above, diamine (2) is treated with Boc-ON (6) toprepare compound (7) in which one of 2 amino groups has been protectedwith tert-butoxycarbonyl group. The resultant compound (7) reacts withcarboxylic acid (5) and affords compound (8). Compound (8) issuccessively treated with an acid to give compound (9). Compound (9)then reacts with the carboxylic acid (3), giving compound (1) accordingto the present invention. Compound (7) can be prepared under thefollowing conditions. The reaction is conducted at −10° C. to 40° C. inthe presence of triethylamine in a solvent such as dichloromethane.Reaction of compound (7) with the mixed acid anhydride, acid halide oractivated ester of the carboxylic acid (5) is carried out using the samereagents and reaction conditions as those described in PreparationProcess 1, whereby compound (8) can be prepared. The resultant compound(8) is treated with trifluoroacetic acid or the like at −20° C. to 70°C., whereby amine (9) can be prepared. In the reaction of the resultantamine (9) with carboxylic acid (3), the same reagents and conditions asthose described in Preparation Process 1 may be used.

[0161] By the way, the tert-butoxycarbonyl group of compound (7) may bereplaced by other amino-protecting groups. In this case, reagent (6) isalso changed to other reagents, and reaction conditions and the likeaccording to the reagents must be used. As examples of other protectinggroups for amino groups, may be mentioned ordinary acyl-type protectinggroups, namely, alkanoyl groups such as an acetyl group, alkoxycarbonylgroups such as methoxycarbonyl and ethoxycarbonyl groups,arylmethoxycarbonyl groups such as benzyloxycarbonyl,p-methoxybenzyloxycarbonyl and p- or o-nitrobenzyloxycarbonyl groups,arylmethyl groups such as benzyl and triphenylmethyl groups, aroylgroups such as a benzoyl group, and arylsulfonyl groups such as2,4-dinitrobenzenesulfonyl and o-nitrobenzenesulfonyl groups. Theseprotecting groups may be chosen for use according to the nature and thelike of the compound of which amino group is to be protected. Uponleaving such a protecting group, reagents and conditions may be employedaccording to the protecting group.

[0162] [Preparation Process 3]

[0163] Compound (1) according to the present invention can be preparedby reacting diamine (2) with sulfonyl halide (10).

[0164] wherein Q¹, Q², Q³, Q⁴, R¹ and R² have the same meanings asdefined above, T¹ represents a sulfonyl group, and X represents ahalogen atom.

[0165] Diamine (2) reacts with sulfonyl halide (10) at −10° C. to 30° C.in the presence of a base such as triethylamine in an inert solvent,giving compound (4). The inert solvent and base may be suitably chosenfor use from those described in Preparation Process 1. The resultantcompound (4) is condensed with carboxylic acid (5) using the reagentsand conditions described in Preparation Process 1, whereby compound (1)according to the present invention can be prepared. Sulfonyl halide (10)may be synthesized in a proper base in accordance with the publiclyknown process (WO96/10022, WO00/09480) or a process according to it.

[0166] [Preparation Process 4]

[0167] Compound (1) according to the present invention can also beprepared in accordance with the following process:

[0168] wherein Q¹, Q², Q³, Q⁴, R¹, R² and X have the same meanings asdefined above, and T¹ represents a sulfonyl group.

[0169] More specifically, amine (9) may react with sulfonyl halide (10)at −10° C. to 30° C. in the presence of a base in an inert solvent,giving compound (1). The inert solvent and base may be suitably chosenfor use from those described in Preparation Process 1.

[0170] [Preparation Process 5]

[0171] In the compounds (1) according to the present invention,geometrical isomers of trans-form and cis-form in the relation betweenposition 1 and position 2 are present when Q³ is the following group:

[0172] wherein R⁹, R¹⁰ and Q⁵ have the same meanings as defined above,and numerals 1 and 2 indicate positions.

[0173] The preparation processes of the compounds (1) having thetrans-form and the cis-form in Q³ will hereinafter be described.

[0174] <Preparation Process of Trans-Form>

[0175] wherein Q⁵, R⁹ and R¹⁰ have the same meanings as defined above.

[0176] As an example of preparation of trans-diol (12a) from cyclicalkene (11), conversion from, for example, cyclohexene totrans-cyclohexanediol (Organic Synthesis, 1995, Vol. III, p. 217) isknown. As an example of preparation of trans-diamine (2a) fromtrans-diol (12a), conversion from trans-cyclopentanediol totrans-cyclopentanediamine (WO98/30574) is reported. Trans-diamine (2a)can be prepared from te cyclic alkene (11) according to these reports.

[0177] Trans-diamine (2a) prepared in accordance with theabove-described process can be converted into trans-compound (1) by anyof the above-described Preparation Processes 1 to 4.

[0178] <Preparation Process of Cis-Form>

[0179] wherein Q⁵, R⁹ and R¹⁰ have the same meanings as defined above.

[0180] As an example of preparation of cis-diol (12b) from cyclic alkene(11), conversion from cyclohexene to cis-cyclohexanediol (J. Org. Chem.,1998, Vol. 63, p. 6094) is known. As an example of preparation ofcis-diamine (2b) from cis-diol (12a), conversion fromcis-cyclopentanediol to cis-cyclopentanediamine (WO98/30574) isreported. Cis-diamine (2b) can be prepared from cyclic alkene (11)according to these reports.

[0181] Cis-diamine (2b) prepared in accordance with the above-describedprocess can be converted into the cis-compound (1) by any of theabove-described Preparation Processes 1 to 4.

[0182] [Preparation Process 6]

[0183] As described above, either cis-form or trans-form generated in Q³may be present in the compounds (1) according to the present invention,and so geometrical isomers are present. Further, optical isomers may bepresent in the respective geometrical isomers. The preparation processof an optically active compound will hereinafter be described.

[0184] wherein Q⁵, R¹, R², R⁹ and R¹⁰ have the same meanings as definedabove, and R⁵⁰ represents a protecting group for amino group.

[0185] With respect to the preparation process of optically activeaminoalcohol derivative (15) of 1,2-trans-form, for example, thepreparation process of optically active 1,2-trans-2-aminocyclopentanolfrom cyclopentene oxide or the preparation process of optically active1,2-trans-2-aminocyclohexanol from cyclohexene oxide is known(Tetrahedron: Asymmetry, 1996, Vol. 7, p. 843; J. Org. Chem., 1985, Vol.50, p. 4154; J. Med. Chem., 1998, Vol. 41, p. 38). When the amino groupof optically active aminoalcohol derivative (15) prepared by such analready known process or by applying such a process reacts with a properprotecting reagent, compound (16) can be produced. As a protecting groupcorresponding to R⁵⁰ in compound (16), is preferred, among the ordinaryacyl type protecting groups, an alkoxycarbonyl group such asmethoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group, anarylmethoxycarbonyl group such as benzyloxycarbonyl,p-methoxybenzyloxycarbonyl or p- or o-nitrobenzyloxycarbonyl group, oran arylsulfonyl group such as 2,4-dinitrobenzenesulfonyl oro-nitrobenzenesulfonyl group. When the amino group is protected with,for example, a tert-butoxycarbonyl group, aminoalcohol derivative (15)may react with di-tert-butyl dicarbonate at −78° C. to 50° C. in aninert solvent, giving compound (16). The inert solvent may be suitablychosen for use from those described in Preparation Process 1.

[0186] Compound (16) may react with methanesulfonyl chloride at −78° C.to 50° C. in the presence of a base in an inert solvent, giving compound(17). The inert solvent may be suitably chosen for use from thosedescribed in Preparation Process 1. As the base, is preferred an organicbase such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, N-methyl-morpholine, diisopropylethylamine ordiazabicyclo[5.4.0]-undec-7-ene (DBU).

[0187] Compound (17) may react with sodium azide at −10° C. to 150° C.in a proper solvent, giving compound (18). As the solvent, an amidesolvent such as N,N-dimethyl-formamide, N,N-dimethylacetamide orN-methylpyrrolidin-2-on, an alcoholic solvent such as methanol orethanol, an etheric solvent such as tetrahydrofuran, 1,2-dimethoxyethaneor dioxane, benzenoid solvent such as toluene, a carbon halogenide suchas dichloromethane, chloroform or carbon tetrachloride, acetone,dimethyl sulfoxide, or a mixed solvent of such a solvent with water issuitable.

[0188] As a process for converting azide derivative (18) into compound(7a), there are many processes such as a process of conductinghydrogenation with a palladium catalyst, Raney nickel catalyst orplatinum catalyst, a reaction using a reducing agent such as lithiumaluminum hydride, sodium borohydride or zinc borohydride, a reactionusing zinc in the presence of nickel chloride or cobalt chloride, and areaction using triphenylphosphine. Suitable reaction conditions may beselected according to the nature of the compound. For example, azidederivative (18) is hydrogenated at a temperature of −10° C. to 70° C.using 1 to 20% palladium on carbon as a catalyst in a proper solvent,whereby compound (7a) can be prepared. The hydrogen pressure may beraised higher than atmospheric pressure. As the solvent, an alcoholicsolvent such as methanol or ethanol, an etheric solvent such astetrahydrofuran, 1,2-dimethoxyethane or dioxane, an amide solvent suchas N,N-dimethylformamide, N,N-dimethylacetamide orN-methylpyrrolidin-2-on, an ester solvent such as ethyl acetate, aceticacid, hydrochloric acid, water, or a mixed solvent thereof is suitable.

[0189] Optically active amine (7a) prepared in accordance with theabove-described process can be converted to optically active compound(1) in accordance with the above-described Preparation Process 2.Antipode (1) of optically active substance (1) obtained from opticallyactive amine (7a) may also be prepared in accordance with a similarprocess.

[0190] Optically active compound (1) may be prepared by separatingracemic compound (1) through a column composed of an optically activecarrier. It is also possible to separate intermediate (2), (4), (7), (8)or (9) for preparing racemic compound (1) through a column composed ofan optically active carrier to isolate optically active intermediate(2), (4), (7), (8) or (9), and then prepare optically active compound(1) in accordance with any of Preparation Processes 1 to 4. As a processfor isolating optically active intermediate (1), (2), (4), (7), (8) or(9), a process of fractionally crystallizing a salt with an opticallyactive carboxylic acid, or a process of fractionally crystallizing asalt with an optically active base on the contrary may be used.

[0191] The following amines (4) used in the above-described PreparationProcesses 1 to 4

HN(R¹)-Q³-N(R²)-T¹-Q⁴   (4)

[0192] wherein R¹, R², Q³, Q⁴ and T¹ have the same meanings as definedabove, or the following amines (9):

Q¹-Q²-C(═O)—N(R¹)-Q³-NHR²   (9)

[0193] wherein R¹, R², Q¹, Q² and Q³ have the same meanings as definedabove, are useful compounds from a viewpoint of intermediates forpreparing compounds (1) according to the present invention.

[0194] Optically active amines (7a) are also useful intermediates. Inparticular, the following amine (7b) can be converted into such anoptically active compound (1a) as described below in accordance with theabove Preparation Process 2. Compound (1a) can be further converted intoderivatives having a carboxyl group, amide group or the like byconverting the ester group on the cyclohexane ring of the compound.

[0195] wherein Boc has the same meaning as defined above.

[0196] Specific preparation processes and FXa-inhibiting effects of theethylenediamine derivatives according to the present invention willhereinafter be described.

EXAMPLES

[0197] In this embodiment, the ethylenediamine derivatives according tothe present invention are named as substituted alkanediamines. Forexample, the following compound:

[0198] is named(±)-trans-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediamine.

Referential Example 1 4-[(tert-Butoxycarbonyl)amino]pyridine

[0199]

[0200] 4-Aminopyridine (10 g) was dissolved in tetrahydrofuran (500 ml),di-tert-butyl dicarbonate (25.5 g) was added to the solution, and themixture was stirred at room temperature for 10 minutes. The resultantreaction mixture was concentrated under reduced pressure, and depositedsolids were washed with hexane to obtain the title compound (16.9 g) asa colorless solid.

[0201]¹H-NMR (CDCl₃) δ: 1.53(9H,s), 6.86(1H,br.s), 7.30(2H,dd,J=1.5,4.9Hz), 8.44(2H,dd,J=1.5,4.9 Hz). MS (FAB) m/z: 195(M+H)⁺.

Referential Example 2 4-[(tert-Butoxycarbonyl)amino]-3-mercaptopyridine

[0202]

[0203] 4-[(tert-Butoxycarbonyl)amino]pyridine (61.6 g) was dissolved intetrahydrofuran (2,000 ml), and the solution was stirred at −78° C. for10 minutes. A hexane solution (1.59 mol/l, 500 ml) of n-butyllithium wasadded dropwise to the solution, and the mixture was stirred for 10minutes and then for 2 hours with ice cooling. After the reactionmixture was cooled to −78° C., sulfur powder (12.2 g) was added, and theresultant mixture was warmed to room temperature and stirred for 1 hour.Water (1,000 ml) was added to the reaction mixture to separate a waterlayer. After 3N hydrochloric acid was added to the water layer to adjustthe pH of the water layer to 3 to 4, dichloromethane was added toseparate an organic layer. The organic layer was dried over anhydroussodium sulfate, and the solvent was distilled off under reducedpressure. The-residue was purified by column chromatography on silicagel (dichloromethane:methanol=50:1) to obtain the title compound (33.2g) as a pale yellow foamy substance.

[0204]¹H-NMR (DMSO-d₆) δ: 1.52(9H,s), 7.89(1H,d,J=6.4 Hz),7.99(1H,d,J=6.4 Hz), 8.20(1H,s), 9.91(1H,br.s). MS (FAB) m/z: 227(M+H)⁺.

Referential Example 3 Thiazolo[5,4-c]pyridine

[0205]

[0206] 4-[(tert-Butoxycarbonyl)amino]-3-mercaptopyridine (33.2 g) wasdissolved in formic acid (250 ml), and the solution was heated underreflux for 3 days. The reaction mixture was concentrated under reducedpressure, and a 5N aqueous solution (100 ml) of potassium hydroxide andether were added to the residue to separate an organic layer. Theorganic layer was dried over anhydrous sodium sulfate, and the solventwas then distilled off under reduced pressure. The residue was purifiedby column chromatography on silica gel (dichloromethane:methanol=25:1)to obtain the title compound (9.03 g) as a colorless solid.

[0207]¹H-NMR (CDCl₃) δ: 8.05(1H,d,J=5.4 Hz), 8.70(1H,d,J=5.4 Hz),9.23(1H,s), 9.34(1H,s). MS (FAB) m/z: 137(M+H)⁺.

Referential Example 4 5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

[0208]

[0209] Thiazolo[5,4-c]pyridine (1.61 g) was dissolved inN,N-dimethylformamide (50 ml), and to the solution methyl iodide (1.50ml) was added, the resultant mixture was stirred at 80° C. for 4 hours.The reaction mixture was concentrated under reduced pressure, and theresidue was dissolved in methanol (100 ml), sodium borohydride (1.53 g)was added, and the resultant mixture was stirred at room temperature for1 hour. The reaction mixture was concentrated under reduced pressure,and a saturated aqueous solution of potassium carbonate and ether wereadded to the residue to separate an organic layer. The organic layer wasdried over anhydrous sodium sulfate., and the solvent was distilled offunder reduced pressure. The residue was purified by columnchromatography on silica gel (dichloromethane:methanol=25:1) to obtainthe title compound (1.28 g) as a pale yellow oil.

[0210]¹H-NMR (CDCl₃) δ: 2.52(3H,s), 2.83(2H,t,J=5.9 Hz), 2.98(2H,t,J=5.9Hz), 3.70(2H,s), 8.63(1H,s). MS (FAB) m/z: 155(M+H)⁺.

Referential Example 5 Lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxylate

[0211]

[0212] 5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (6.43 g) wasdissolved in absolute tetrahydrofuran (200 ml), to the solutionn-butyllithium (1.47N hexane solution, 34.0 ml) was added dropwise at−78° C., and the resultant mixture was stirred for 40 minutes. Aftercarbon dioxide gas was blown into the reaction mixture at −78° C. for 1hour, the reaction mixture was warmed to room temperature and thenconcentrated under reduced pressure to obtain the title compound (9.42g) as pale brown foamy solids.

[0213]¹H-NMR (DMSO-d₆) δ: 2.37(3H,s), 2.64-2.77(4H,m), 3.54(2H,s). MS(FAB) m/z: 199(M+H)⁺.

Referential Example 65-Ethoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine

[0214]

[0215] Phosphorus pentasulfide (500 g) was suspended in formamide (3,000ml) with ice cooling, and the suspension was stirred overnight. Waterand diethyl ether were added to the reaction mixture, and an organiclayer was separated and dried over anhydrous magnesium sulfate, and thesolvent was distilled off to obtain a yellow oil. After the oil wasdissolved in n-butanol (350 ml), and3-chloro-1-ethoxycarbonylpiperidin-4-one (150 g) synthesized accordingto the process described in literature (Tetrahedron, 1983, Vol. 39, p.3767) was added to the solution, the resultant mixture was stirred at100° C. for 2.5 hours. The reaction mixture was filtered through Celite.The resultant filtrate was washed with a saturated aqueous solution ofsodium hydrogencarbonate and saturated saline, and then dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, and the residue was purified by column chromatography onsilica gel (dichloromethane-ethyl acetate:hexane=1:2) to obtain thetitle compound (79.0 g) as a brown oil.

[0216]¹H-NMR (CDCl₃) δ: 1.30(3H,t,J=7.3 Hz), 2.96(2H,br.s),3.82(2H,br.s), 4.19(2H,q,J=7.3 Hz), 4.73(2H,br.s), 8.68(1H,s). MS (FAB)m/z: 213(M+H)⁺.

Referential Example 75-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine

[0217]

[0218] A 3.5N aqueous solution (250 ml) of sodium hydroxide was added to5-ethoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (33.5 g), andthe mixture was heated under reflux overnight. After the reactionmixture was cooled to room temperature, di-tert-butyl dicarbonate (103g) was added with ice cooling, and the mixture was stirred overnight atroom temperature. After 3N hydrochloric acid was added to the reactionmixture to adjust the pH thereof to 1 to 2, dichloromethane was added.After separation of an organic layer, the organic layer was washedsuccessively with an aqueous solution of sodium hydrogencarbonate andsaturated saline and then dried-over anhydrous sodium sulfate. After theorganic layer was concentrated under reduced pressure, the resultantresidue was purified by column chromatography on silica gel (ethylacetate:hexane=1:2) to obtain the title compound (21.1 g) as a palebrown oil.

[0219]¹H-NMR (CDCl₃) δ: 1.49(9H,s), 2.94(2H,br.s), 3.76(2H,br.s),4.68(2H,s), 8.67(1H,s). MS (FAB) m/z: 241(M+H)⁺.

Referential Example 85-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxylicacid

[0220]

[0221] To a solution of5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (845 mg)in absolute tetrahydrofuran (20 ml), n-butyllithium (1.65N hexanesolution, 2.13 ml) was added dropwise at −78° C., and the mixture wasstirred for 30 minutes with ice cooling. After passing carbon dioxidegas into the reaction mixture at −78° C. for 1 hour, the reactionmixture was warmed to room temperature. A 5N aqueous solution of sodiumhydroxide and diethyl ether were added to the reaction mixture toseparate a water layer. 6N Hydrochloric acid was added to the waterlayer to adjust the pH thereof to 1 to 2. After addition ofdichloromethane, an organic layer separated was washed with saturatedsaline and dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure to obtain the title compound (562mg) as a pale yellow foamy substance.

[0222]¹H-NMR (CDCl₃) δ: 1.50(9H,s), 3.00(2H,br.s), 3.78(2H,br.s),4.74(2H,br.s). MS (FAB) m/z: 241(M+H)⁺.

Referential Example 92-Amino-5-tert-butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine

[0223]

[0224] 1-tert-Butoxycarbonyl-4-piperidone (40.0 g) was dissolved incyclohexane (80 ml), and to the solution p-toluenesulfonic acidmonohydrate (191 mg) and pyrrolidine (17.6 ml) were added. The mixturewas heated under reflux for 2 hours while removing water using aDean-Stark trap. After the reaction mixture was concentrated underreduced pressure, the residue was dissolved in methanol (60 ml), andsulfur powder (6.42 g) was added. A methanol solution (10 ml) ofcyanamide (8.44 g) was slowly added dropwise with ice cooling, and themixture was stirred at room temperature for 5 hours. Precipitated solidmaterials were collected by filtration to obtain the title compound(31.0 g) as a pale yellow solid.

[0225]¹H-NMR (DMSO-d₆) δ: 1.41(9H,s), 2.40-2.46(2H,m), 3.57(2H,t,J=5.6Hz), 4.29(2H,s), 6.79(2H,s). MS (EI) m/z: 255(M⁺).

Referential Example 102-Bromo-5-tert-butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine

[0226]

[0227] Copper(II) bromide (1.05 g) was suspended inN,N-dimethylformamide, and tert-butyl nitrite (0.696 ml) was added.After2-amino-5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine(1.00 g) was added with ice cooling, the reaction mixture was heated andstirred at 40° C. for 30 minutes. The reaction mixture was concentratedunder reduced pressure, and the residue was purified by columnchromatography on silica gel (ethyl acetate:hexane=1:5) to obtain thetitle compound (568 mg) as a yellow solid.

[0228]¹H-NMR (CDCl₃) δ: 1.48(9H,s), 2.85(2H,br.s), 3.72(2H,t,J=5.6 Hz),4.56(2H,br.s). MS (FAB) m/z: 319(M+H)⁺.

Referential Example 11 2-Bromo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinetrifluoroacetate

[0229]

[0230]2-Bromo-5-tert-butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine(890 mg) was dissolved in dichloromethane (2 ml), and to the solutiontrifluoroacetic acid (15 ml) was added, and the mixture was stirred atroom temperature for 1 minute. The reaction mixture was concentratedunder reduced pressure, and diethyl ether was added to the residue.Precipitated solid materials were collected by filtration to obtain thetitle compound (867 mg) as a colorless solid.

[0231]¹H-NMR (DMSO-d₆) δ: 2.98(2H,t,J=6.1 Hz), 3.72(2H,t,J=6.1 Hz),4.35(2H,s), 9.53(2H,br.s). MS (FAB) m/z: 219(M+H)⁺.

Referential Example 122-Bromo-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine

[0232]

[0233] 2-Bromo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinetrifluoroacetate (422 mg) was suspended in dichloromethane (10 ml),triethylamine (0.356 ml) was added, and the mixture was stirred at roomtemperature for 15 minutes. Acetic acid (0.216 ml) and an aqueoussolution (35% solution, 0.202 ml) of formaldehyde were added to thereaction mixture, and the resultant mixture was stirred at roomtemperature for 2 minutes. Sodium triacetoxyborohydride (428 mg) wasadded to the reaction mixture, and the resultant mixture was stirred atroom temperature for 1 hour. A 1N aqueous solution (10 ml) of sodiumhydroxide was added to the reaction mixture and an organic layer wasseparated. After the organic layer was dried over anhydrous sodiumsulfate, the solvent was distilled off under reduced pressure. Theresidue was purified by column chromatography on silica gel(dichloromethane:methanol=100:1) to obtain the title compound (286 mg)as a pale brown oil.

[0234]¹H-NMR (CDCl₃) δ: 2.49(3H,s), 2.79(2H,t,J=5.8 Hz),2.88-2.93(2H,m), 3.58(2H,s). MS (FAB) m/z: 233(M+H)⁺.

Referential Example 13 Lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxylate

[0235]

[0236] 2-Bromo-5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine (531mg) was dissolved in absolute diethyl ether (20 ml), n-butyllithium(1.54N hexane solution, 1.63 ml) was added dropwise at −78° C., and themixture was stirred for 30 minutes with ice cooling. After passingcarbon dioxide into the reaction mixture at −78° C. for 1 hour, themixture was warmed to room temperature. The reaction mixture wasconcentrated under reduced pressure to obtain the title compound (523mg) as a pale brown solid.

[0237]¹H-NMR (DMSO-d₆) δ: 2.37(3H,s), 2.64-2.77(4H,m), 3.54(2H,s). MS(FAB) m/z: 199(M+H)⁺.

Referential Example 14 4-Ethoxycarbonyl-2-(trans-styryl)oxazole

[0238]

[0239] Synthesis was conducted in accordance with the report (J. Org.Chem., 1996, Vol. 61, p. 6496) by Panek et al. Sodium hydrogencarbonate(22.8 g) and ethyl bromopyruvate (10.5 ml) were added to a solution ofcinnamamide (10.0 g) in tetrahydrofuran (250 ml) at room temperature,and the mixture was heated under reflux for 48 hours. The reactionmixture was allowed to cool to room temperature, filtered through Celiteand then concentrated under reduced pressure to obtain residue.Trifluoroacetic anhydride (30 ml) was added to a solution of thisresidue in tetrahydrofuran (30 ml) at 0° C., and the mixture wasgradually warmed to room temperature. After the mixture was stirred for63 hours, a saturated aqueous solution (500 ml) of sodiumhydrogencarbonate and ethyl acetate (150 ml) were added to the reactionmixture, and an organic layer was separated. The water layer wasextracted with ethyl acetate (150 ml). The organic layers were combined,washed with saturated saline (150 ml), dried over anhydrous sodiumsulfate and then concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel (hexane:ethylacetate=5:1→3:1) to obtain the title compound (10.9 g) as a colorlesssolid.

[0240]¹H-NMR (CDCl₃) δ: 1.41(3H,t,J=7.0 Hz), 4.42(2H,q,J=7.0 Hz),6.96(1H,d,J=16.6 Hz), 7.30-7.40(3H,m), 7.53(2H,d,J=6.8 Hz),7.63(1H,d,J=16.6 Hz), 8.20(1H,s).

Referential Example 15 4-Formyl-2-(trans-styryl)oxazole

[0241]

[0242] Diisobutylaluminum hydride (1.0N hexane solution, 66 ml) wasadded dropwise to a solution of 4-ethoxycarbonyl-2-(trans-styryl)oxazole(8.57 g) in dichloromethane (80 ml) at −78° C. After 15 minutes,methanol (11 ml) was added dropwise, and the mixture was warmed to roomtemperature over 1 hour. The reaction mixture was filtered throughCelite, and the resultant pasty substance was dissolved in ethyl acetate(200 ml) and a saturated aqueous solution (200 ml) of ammonium chloridewas added, and an organic layer was separated. The water layer was thenextracted with dichloromethane (2×100 ml). The resultant organic layerswere collected and washed with a saturated aqueous solution (100 ml) ofsodium hydrogencarbonate and saturated saline (100 ml), combined withthe filtrate obtained by the filtration through Celite and then driedover anhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by column chromatography onsilica gel (dichloromethane:ethylacetate=5:1→dichloromethane:methanol=10:1) to obtain the title compound(5.86 g) as colorless needle crystals.

[0243]¹H-NMR (CDCl₃) δ: 6.96(1H,d,J=16.6 Hz), 7.35-7.45(3H,m),7.56(2H,d,J=6.4 Hz), 7.67(1H,d,J=16.6 Hz), 8.26(1H,s), 9.98(1H,s). MS(FAB) m/z: 200(M+H)⁺.

Referential Example 16 2-(trans-Styryl)-4-vinyloxazole

[0244]

[0245] n-Butyllithium (1.54N hexane solution, 14.2 ml) was addeddropwise to a solution of methyl-triphenylphosphonium bromide (8.16 g)in tetrahydrofuran (80 ml) at 0° C., and the mixture was stirred at roomtemperature for 30 minutes. The reaction mixture was cooled again to 0°C., a solution of 4-formyl-2-(trans-styryl)oxazole (3.64 g) intetrahydrofuran (20 ml) was added, and the mixture was warmed to roomtemperature. After stirring for 2 hours, water (200 ml) and ethylacetate (100 ml) were added and an organic layer was separated. Thewater layer was extracted with ethyl acetate (50 ml). After the organiclayers were combined, washed with saturated saline (100 ml) and driedover anhydrous sodium sulfate, the solvent was distilled off underreduced pressure. The residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=4:1→3:1) to obtain the title compound(2.84 g) as a pale yellow oil.

[0246]¹H-NMR (CDCl₃) δ: 5.33(1H,dd,J=1.5,10.7 Hz), 5.98(1H,dd,J=1.5,17.6Hz), 6.56(1H,dd,J=10.7,17.6 Hz), 6.95(1H,d,J=16.6 Hz), 7.31-7.42(3H,m),7.49-7.56(4H,m). MS (FAB) m/z: 198(M+H)⁺.

Referential Example 17 4-(2-Hydroxyethyl)-2-(trans-styryl)oxazole

[0247]

[0248] 9-Borabicyclo[3.3.1]nonane (0.5N tetrahydrofuran solution, 158ml) was added to a solution of 2-(trans-styryl)-4-vinyloxazole (13.0 g)in tetrahydrofuran (500 ml) at 0° C., and the mixture was stirred atroom temperature for 15 hours. Water (10 ml), a 3N aqueous solution (80ml) of sodium hydroxide and aqueous hydrogen peroxide (80 ml) weresuccessively added dropwise to the reaction mixture at 0° C., and themixture was stirred at room temperature for 6 hours. After water (600ml) and ethyl acetate (200 ml) were added to the resultant reactionmixture to separate an organic layer, the water layer was extracted withethyl acetate (200 ml). After the organic layers were collected, washedwith saturated saline (200 ml) and dried over anhydrous sodium sulfate,the solvent was distilled off under reduced pressure. The residue waspurified by column chromatography on silica gel (hexane:ethylacetate=2:1→ethyl acetate alone) to obtain the title compound (14.1 g)as a colorless solid.

[0249]¹H-NMR (CDCl₃) δ: 2.69(1H,br.s), 2.80(2H,t,J=5.6 Hz),3.90-3.97(2H,m), 6.91(1H,d,J=16.6 Hz), 7.30-7.42(4H,m), 7.43-7.56(3H,m).MS (FAB) m/z: 216(M+H)⁺.

Referential Example 18N-[2-[2-(trans-Styryl)oxazol-4-yl]ethyl]phthalimide

[0250]

[0251] Phthalimide (200 mg), triphenylphosphine (357 mg) and diethylazodicarboxylate (0.214 ml) were added to a solution of4-(2-hydroxyethyl)-2-(trans-styryl)oxazole (292 mg) in tetrahydrofuran(15 ml) at room temperature, and the mixture was stirred for 4 hours.The solvent of the reaction mixture was distilled off under reducedpressure. The residue was purified by column chromatography on silicagel (hexane:ethyl acetate=3:1) to obtain the title compound (447 mg) asa colorless solid.

[0252]¹H-NMR (CDCl₃) δ: 2.98(2H,t,J=7.2 Hz), 4.03(2H,t,J=7.2 Hz),6.88(1H,d,J=16.6 Hz), 7.28-7.45(5H,m), 7.48(2H,d,J=7.3 Hz),7.71(2H,dd,J=2.9,5.4 Hz), 7.84(2H,dd,J=2.9,5.4 Hz). MS (FAB) m/z:345(M+H)⁺.

Referential Example 194-[2-(tert-Butoxycarbonylamino)ethyl]-2-(trans-styryl)oxazole

[0253]

[0254] After hydrazine monohydrate (1.50 ml) was added to a solution ofN-[2-[2-(trans-styryl)oxazol-4-yl]-ethyl]phthalimide (6.40 g) in ethanol(150 ml) at room temperature, and the mixture was stirred for 1 hour,hydrazine monohydrate (0.500 ml) was added again at room temperature,and the mixture was stirred for 2 hours. Dichloromethane (150 ml), asaturated solution (150 ml) of sodium hydrogencarbonate anddi-tert-butyl dicarbonate (13.4 g) were added to the reaction mixture atroom temperature. After stirring for 30 minutes, a water layer wasseparated and extracted with dichloromethane (50 ml). The resultantorganic layers were combined and dried over anhydrous sodium sulfate,and the solvent was then distilled off under reduced pressure. Theresidue was purified by column chromatography on silica gel(hexane:ethyl acetate=2:1→1:1) to obtain the title compound (5.06 g) asa colorless solid.

[0255]¹H-NMR (CDCl₃) δ: 1.45(9H,s), 2.75(2H,t,J=6.6 Hz),3.46(2H,dt,J=5.9,6.6 Hz), 4.92(1H,br.s), 6.91(1H,d,J=16.6 Hz),7.29-7.45(4H,m), 7.48(1H,d,J=16.6 Hz), 7.52(2H,d,J=7.3 Hz). MS (FAB)m/z: 315(M+H)⁺, 259(M-isobutene+H)⁺, 315(M-Boc+H)⁺.

Referential Example 205-(tert-Butoxycarbonyl)-2-(trans-styryl)-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine

[0256]

[0257] Paraformaldehyde (54.5 mg) and p-toluenesulfonic acid (7.2 mg)were added to a solution of4-[2-(tert-butoxycarbonylamino)ethyl]-2-(trans-styryl)oxazole (190 mg)in toluene (15 ml) at room temperature. After heating under reflux for 1hour, the reaction mixture was allowed to cool, and ethyl acetate (15ml) and a saturated aqueous solution (15 ml) of sodiumhydrogen-carbonate were added to the reaction mixture to separate anorganic layer. After the water layer was extracted with ethyl acetate(10 ml), the resultant organic layers were combined and dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=3:1→2:1) to obtain the title compound(153 mg) as a colorless oil.

[0258]¹H-NMR (CDCl₃) δ: 1.50(9H,s), 2.67(2H,br.s), 3.73(2H,br.s),4.55(2H,s), 6.90(1H,d,J=16.1 Hz), 7.29-7.42(3H,m), 7.46(1H,d,J=16.1 Hz),7.52(2H,d,J=7.3 Hz). MS (FAB) m/z: 327(M+H)⁺, 271(M-isobutene+H)⁺,227(M-Boc+H)⁺.

Referential Example 215-(tert-Butoxycarbonyl)-2-formyl-4,5,6,7-tetrahydro-oxazolo[5,4-c]pyridine

[0259]

[0260] Acetone (8.0 ml), water (4.0 ml), N-methyl-morpholine oxide (577mg) and osmium tetroxide (0.039 M, 3.20 ml) were added to a solution of5-(tert-butoxy-carbonyl)-2-(trans-styryl)-4,5,6,7-tetrahydrooxazolo-[5,4-c]pyridine(803 mg) in tetrahydrofuran (16 ml) at room temperature, and the mixturewas stirred overnight. Ethyl acetate (50 ml) and a 10% aqueous solution(50 ml) of sodium thiosulfate were added to the reaction mixture toseparate an organic layer. The water layer was then extracted with ethylacetate (30 ml). After the resultant organic layers were combined anddried over anhydrous sodium sulfate, the solvent was distilled off underreduced pressure. Methanol (8.0 ml), water (8.0 ml) and sodiummetaperiodate (790 mg) were added to a solution of the residue intetrahydrofuran (16 ml). After stirring for 3 hours, ethyl acetate (30ml) and water (50 ml) were added to the reaction mixture to separate anorganic layer. The water layer was extracted with ethyl acetate (20 ml).After the resultant organic layers were combined, washed with asaturated solution (50 ml) of sodium hydrogencarbonate and dried overanhydrous sodium sulfate, the solvent was distilled off under reducedpressure. The residue was purified by column chromatography on silicagel (hexane:ethyl acetate=4:1→2:1) to obtain the title compound (234 mg)as a colorless amorphous substance. Since this aldehyde was unstable, itwas immediately used in the next reaction.

[0261]¹H-NMR (CDCl₃) δ: 1.49(9H,s), 2.77(2H,br.s), 3.77(2H,br.s),4.62(2H,s), 9.70(1H,s).

Referential Example 225-(tert-Butoxycarbonyl)-2-methoxycarbonyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine

[0262]

[0263] Sodium cyanide (220 mg) and manganese dioxide (780 mg) were addedto a solution of5-(tert-butoxycarbonyl)-2-formyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine(225 mg) in methanol (9.0 ml) at room temperature. After stirring for 30minutes, the reaction mixture was filtered through Celite with ethylacetate. The filtrate was washed with water (50 ml) and saturated saline(50 ml) and dried over anhydrous sodium sulfate. The solvent was thendistilled off under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (hexane:ethyl acetate=3:2→1:1) toobtain the title compound (120 mg) as a colorless amorphous substance.

[0264]¹H-NMR (CDCl₃) δ: 1.49(9H,s), 2.73(2H,br.s), 3.74(2H,br.s),4.01(3H,s), 4.59(2H,s). MS (FAB) m/z: 283(M+H)⁺.

Referential Example 232-Methoxycarbonyl-5-methyl-4,5,6,7-tetrahydrooxazolo-[5,4-c]pyridine

[0265]

[0266] Trifluoroacetic acid (15 ml) was added to a solution of5-(tert-butoxycarbonyl)-2-methoxycarbonyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine(500 mg) in dichloromethane (15 ml) at room temperature, and the mixturewas stirred for 10 minutes. The reaction mixture was concentrated underreduced pressure, and dichloromethane (20 ml), triethylamine (0.495 ml),acetic acid (205 ml), formalin (0.230 ml) and sodiumtriacetoxyborohydride (570 mg) were added to the resultant residue atroom temperature. After stirring for 15 minutes, dichloromethane (20 ml)and a saturated aqueous solution (50 ml) of sodium hydrogencarbonatewere added to separate an organic layer. The water layer was extractedwith dichloromethane (3×20 ml). After the resultant organic layers werecombined and dried over anhydrous sodium sulfate, the solvent wasdistilled off under reduced pressure. The residue was purified by columnchromatography on silica gel (chloroform:methanol=20:1→10:1) to obtainthe title compound (257 mg) as a colorless oil.

[0267]¹H-NMR (CDCl₃) δ: 2.52(3H,s), 2.72-2.78(2H,m), 2.78-2.83(2H,m),3.61(2H,t,J=1.7 Hz), 4.00(3H,s). MS (FAB) m/z: 197(M+H)⁺, 165(M-OCH₃)⁺.

Referential Example 24 Lithium5-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]-pyridine-2-carboxylate

[0268]

[0269] Water (6.0 ml) and lithium hydroxide (99.7 mg) were added to asolution of2-methoxycarbonyl-5-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine (800mg) in tetrahydrofuran (24 ml) at room temperature, and the mixture wasstirred for 10 minutes. The reaction mixture was concentrated underreduced pressure to obtain the title compound (825 mg).

[0270]¹H-NMR (DMSO-d6) δ: 2.37(3H,s), 2.47(2H,t,J=5.6 Hz),2.64(2H,t,J=5.6 Hz), 3.43(2H,s).

Referential Example 25 5-Chlorobenzo[b]thiophene-2-carboxylic acid

[0271]

[0272] After 5-chlorobenzo[b]thiophene (2.53 g) was dissolved inabsolute ether (40 ml), and the interior of a vessel was purged withargon, the solution was cooled to −78° C. tert-Butyllithium (1.54Nhexane solution, 9.74 ml) was added dropwise to the solution, and themixture was stirred at the same temperature for 1 hour in total. Thereaction mixture was heated to 0° C. and stirred for 1.5 hours. Thereaction mixture was cooled again to −78° C. and stirred for 1.5 hourswhile blowing carbon dioxide into the interior of the vessel. Thetemperature was returned to room temperature, 0.3N hydrochloric acid(100 ml) and ethyl acetate were added to the reaction mixture toseparate an organic layer. The solvent was distilled off under reducedpressure, and ether was added to the residue. Precipitates werecollected by filtration to obtain the title compound (2.67 g) as acolorless solid.

[0273]¹H-NMR (DMSO-d₆) δ: 7.53(1H,dd,J=8.5,2.2 Hz), 8.07-8.11(3H,m),13.65(1H,br.s). MS (FAB) m/z: 213(M+H)⁺.

Referential Example 26 Methyl 5-chloro-6-fluoroindole-2-carboxylate

[0274]

[0275] A mixture of methyl 3-chloro-4-fluoro-α-azidocinnamate (JapanesePatent Application Laid-Open No. 149723/1995) (1.85 g) and xylene (140ml) was heated under reflux for 1 hour, and the solvent was thendistilled off. The residue was purified by column chromatography onsilica gel (dichloromethane) to obtain the title compound (491 mg) ascolorless powder.

[0276]¹H-NMR (CDCl₃) δ: 3.95(3H,s), 7.13-7.15(1H,m),7.20(1H,dd,J=9.3,0.49 Hz), 7.71(1H,d,J=7.3 Hz), 8.93(1H,br.s) MS (FAB)m/z: 227(M⁺).

Referential Example 27 5-Chloro-6-fluoroindole-2-carboxylic acid

[0277]

[0278] Methyl 5-chloro-6-fluoroindole-2-carboxylate (461 mg) wasdissolved in a mixed solvent of tetrahydrofuran (15 ml), methanol (10ml) and water (10 ml), lithium hydroxide (283 mg) was added at roomtemperature, and the mixture was stirred for 4 hours. The solvent wasdistilled off under reduced pressure, and 1N hydrochloric acid was addedto the residue to weakly acidify it. The resultant powder was collectedby filtration and dried to obtain the title compound (422 mg) ascolorless powder.

[0279]¹H-NMR (CDCl₃) δ: 7.08-7.10(1H,m), 7.34(1H,d,J=9.5 Hz),7.88(1H,d,J=7.6 Hz), 12.04(1H,s), 13.16(1H,s). MS (FAB) m/z: 213(M⁺).

Referential Example 285-(4-Pyridyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine

[0280]

[0281] Trifluoroacetic acid (25 ml) was added to a solution of5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (5.00g) in dichloromethane (25 ml) at room temperature. After stirring for 10minutes, the reaction mixture was concentrated under reduced pressure,and 4-bromopyridine (5.20 g), N,N-dimethylformamide (30 ml) andtriethylamine (15.5 ml) were added to the residue at room temperature,and the mixture was stirred at 150° C. for 2 days and then allowed tocool to room temperature. Colorless precipitates were separated byfiltration, and the filtrate was concentrated under reduced pressure.Thereafter, dichloromethane (50 ml) and a saturated aqueous solution(100 ml) of sodium hydrogencarbonate were added to the residue, and theresultant water layer was saturated with sodium chloride. Afterseparation of an organic layer, the resultant water layer was extractedwith dichloromethane (5×30 ml). After the resultant organic layers werecombined and dried over anhydrous sodium sulfate, the solvent wasdistilled off under reduced pressure. The residue was purified by columnchromatography on silica gel (dichloromethane:methanol=20:1→8:1) toobtain the title compound (2.97 g) as a brown solid.

[0282]¹H-NMR (CDCl₃) δ: 3.07(2H,t,J=5.9 Hz), 3.81(2H,t,J=5.9 Hz),4.61(2H,s), 6.74(2H,t,J=6.5 Hz), 8.30(2H,t,J=6.5 Hz), 8.70(1H,s). MS(ESI) m/z: 218(M+H)⁺.

Referential Example 29 Methyl 5-(4-pyridyl)thiazole-2-carboxylate

[0283]

[0284] 1-Hydroxybenzotriazole monohydrate (805 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.71 g)were added to a solution of lithium 5-(4-pyridyl)thiazole-2-carboxylate(632 mg) in methanol (5.0 ml) at room temperature. After stirring for 4days, the reaction mixture was concentrated under reduced pressure, anddichloromethane (20 ml), a saturated aqueous solution (100 ml) of sodiumhydrogencarbonate and water (100 ml) were added to the residue toseparate an organic layer. The water layer was then extracted withdichloromethane (2×20 ml). After the resultant organic layers werecombined and dried over anhydrous sodium sulfate, the solvent wasdistilled off under reduced pressure. The residue was then purified bycolumn chromatography on silica gel (dichloromethane:acetone=5:1→2:1) toobtain the title compound (353 mg) as a colorless solid.

[0285]¹H-NMR (CDCl₃) δ: 4.05(3H,s), 7.51(2H,d,J=6.1 Hz), 8.32(1H,s),8.71(2H,d,J=6.1 Hz). MS (ESI) m/z: 221(M+H)⁺.

Referential Example 30(±)-cis-N-[(5-Chloroindol-2-yl)carbonyl]-1,2-cyclopropanediamine

[0286]

[0287] 1-Hydroxybenzotriazole monohydrate (377 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (642 mg) anddiisopropylethylamine (1.95 ml) were added tocis-1,2-cyclopropanediamine hydrochloride (J. Med. Chem., 1998, Vol. 41,pp. 4723-4732) (405 mg) and a solution of 5-chloroindole-2-carboxylicacid (546 mg) in N,N-dimethylformamide (10 ml) at room temperature, andthe mixture was stirred for 50 hours. After the reaction mixture wasconcentrated under reduced pressure, dichloromethane (50 ml) and asaturated solution (200 ml) of sodium hydrogencarbonate were added toseparate colorless solid deposited by filtration. An organic layer ofthe filtrate was separated and the water layer was extracted withdichloromethane. After the resultant organic layers were combined anddried over anhydrous sodium sulfate, the solvent was distilled off underreduced pressure to obtain residue. The residue was purified bymedium-pressure flash column chromatography on silica gel(dichloromethane:methanol=100:7→10:1) to obtain the title compound (110mg) as a colorless solid.

[0288]¹H-NMR (DMSO-d₆) δ: 0.44(1H,dd,J=10.7,4.4 Hz),1.11(1H,dd,J=14.0,7.4 Hz), 2.63-2.70(1H,m), 3.07-3.16(1H,m), 6.77(1H,s),6.97(1H,br.s), 7.23(1H,dd,J=8.9,1.8 Hz), 7.36(1H,d,J=8.9 Hz),7.60(1H,s), 9.32(1H,s). MS (FAB) m/z: 250(M+H)⁺.

Referential Example 31 2-Chloro-6,7-dihydro-4H-pyrano[4,3-d]thiazole

[0289]

[0290] 1) Tetrahydro-4H-pyran-4-one (5.0 g) was dissolved in cyclohexane(20 ml), and to the solution pyrrolidine (4.35 ml) and p-toluenesulfonicacid monohydrate (48 mg) were added, and the mixture was heated underreflux for 70 minutes while removing water by a Dean-Stark trap. Thereaction mixture was cooled to room temperature, and the solvent wasdecanted, and the resulting solvent was concentrated under reducedpressure. The residue was dissolved in methanol (15 ml), and sulfurpowder (1.60 g) was added with ice cooling. After 15 minutes, a methanolsolution (10 ml) of cyanamide (2.10 g) was added dropwise over 20minutes, and the mixture was stirred for 3 days. The solvent wasdistilled off under reduced pressure, and the residue was purified bycolumn chromatography on silica gel(dichloromethane:methanol=20:1→10:1→4:1) to obtain2-amino-6,7-dihydro-4H-pyrano[4,3-d]-thiazole (3.97 g) as a brownamorphous substance.

[0291]¹H-NMR (CDCl₃) δ: 2.66-2.70(2H,m), 3.97(2H,t,J=5.6 Hz),4.63(2H,s), 4.94(2H,br.s). MS (FAB) m/z: 157(M+H)⁺.

[0292] 2) Copper(II) chloride (4.10 g) was dissolved in acetonitrile (50ml), and to the solution tert-butyl nitrite (3.93 g) was added in oneportion with ice cooling. After 10 minutes, the compound (3.97 g)obtained in the above-described reaction was added to the mixture overabout 1 hour, and the reaction mixture was stirred at room temperaturefor 1 hour. The reaction mixture was heated to 65° C. and continuouslystirred for 2 hours. After silica gel (20 g) was added to the reactionmixture, the solvent was distilled off under reduced pressure, and theresidue was purified by column chromatography on silica gel(hexane:ethyl acetate=3:1) to obtain the title compound (1.78 g) as ayellow oil.

[0293]¹H-NMR (CDCl₃) δ: 2.85-2.89(2H,m), 4.02(2H,t,J=5.6 Hz),4.73(2H,s). MS (FAB) m/z: 175(M+H)⁺.

Referential Example 32 Lithium6,7-dihydro-4H-pyrano[4,3-d]thiazole-2-carboxylate

[0294]

[0295] 1) 2-Chloro-6,7-dihydro-4H-pyrano[4,3-d]thiazole (1.78 g) wasdissolved in methanol (30 ml), and to the solution 10% palladium oncarbon (300 mg) and sodium acetate (830 mg) were added. The mixture wasstirred for 5 days in a hydrogen stream of 5 atm. After the catalyst wasseparated by filtration, the filtrate was concentrated, and the residuewas subjected to column chromatography on silica gel (hexane:ethylacetate=2:1) to obtain 6,7-dihydro-4H-pyrano[4,3-d]thiazole (1.14 g) asa colorless oil.

[0296]¹H-NMR (CDCl₃) δ: 2.97-3.01(2H,m), 4.04(2H,t,J=5.6 Hz),4.87(2H,s), 8.69(1H,s). MS (FAB) m/z: 142(M+H)⁺.

[0297] 2) After the product (1.14 g) obtained above was dissolved indiethyl ether (30 ml) and cooled to −78° C., 1.6 M butyllithium (6.6 ml)was added to the solution, and the mixture was stirred. After 20minutes, bubbling was conducted with carbon dioxide for 15 minutes. Thereaction mixture was warmed to room temperature and concentrated underreduced pressure to obtain the title compound (1.65 g) as a colorlessamorphous substance.

[0298]¹H-NMR (DMSO-d₆) δ: 2.83(2H,t,J=5.6 Hz), 3.92(2H,t,J=5.6 Hz),4.73(2H,s).

Referential Example 33(±)-cis-N-[(5-Chloroindol-2-yl)carbonyl]-1,2-cyclobutanediamine

[0299]

[0300] The title compound was obtained from cis-1,2-cyclobutanediaminehydrochloride (J. Am. Chem. Soc., 1942, Vol. 64, pp. 2696-2700) in asimilar manner to Referential Example 30.

[0301]¹H-NMR (DMSO-d₆) δ: 1.55-2.20(4H,m), 3.52-3.62(1H,m),4.35-4.50(1H,m), 7.16(1H,dd,J=8.7,2.1 Hz), 7.19(1H,s), 7.42(1H,d,J=8.7Hz), 7.70(1H,d,J=2.1 Hz), 8.36(1H,d,J=7.8 Hz), 11.77(1H,br.s). MS (ESI)m/z: 264(M+H)⁺.

Referential Example 34(±)-cis-N-tert-Butoxycarbonyl-1,2-cyclopentanediamine

[0302]

[0303] cis-1,2-Cyclopentanediamine (W098/30574) (692 mg) was dissolvedin dichloromethane (10 ml), to which triethylamine (1.1 ml) and2-(tert-butoxycarbonyloxy-imino)-2-phenylacetonitrile (493 mg) wereadded, and the mixture was stirred at 0° C. for 1 hour. Thereafter,2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (493 mg) wereadditionally added, and the mixture was stirred at room temperature for7 hours. Water was added to the reaction mixture to separate an organiclayer. The organic layer was washed with saturated saline and dried overanhydrous sodium sulfate. The residue was purified by flash columnchromatography on silica gel (dichloromethane:methanol=9:1) to obtainthe title compound (395 mg) as a pale yellow oil.

[0304]¹H-NMR (CDCl₃) δ: 1.46(9H,s), 1.55-2.00(6H,m), 3.45-3.52(1H,m),3.83-3.90(1H,m), 5.27(1H,br.s). MS (ESI) m/z: 201(M+H)⁺.

Referential Example 35trans-N-[(5-Chloroindol-2-yl)carbonyl)-1,2-cyclopentanediaminehydrochloride

[0305]

[0306] trans-N-tert-Butoxycarbonyl-1,2-cyclopentane-diamine (1.40 g) wasdissolved in N,N-dimethylformamide (15 ml), and to the solution5-chloroindole-2-carboxylic acid (1.64 g),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.68 g) and1-hydroxybenzotriazole monohydrate (473 mg) were added. The mixture wasstirred at room temperature for 23 hours. The solvent was distilled offunder reduced pressure, and dichloromethane and a saturated solution ofsodium hydrogencarbonate were added to the residue to collectprecipitates by filtration. The precipitates were washed with ethylacetate, dichloromethane and methanol. On the other hand, the filtratewas separated to give an organic layer,which was taken out and driedover anhydrous sodium sulfate, and the solvent was then distilled offunder reduced pressure. The residue was purified by medium-pressureflash column chromatography on silica gel(dichloromethane:methanol=19:1) to obtain a pale yellow solid. This paleyellow solid was combined with the precipitates obtained by thefiltration and dissolved in dichloromethane (10 ml), and trifluoroaceticacid (10 ml) was added to stir the mixture at room temperature for 3hours. The solvent was distilled off under reduced pressure, anddichloromethane and a 1N aqueous solution of sodium hydroxide were addedto the residue to collect precipitate by filtration. The organic layerof the filtrate was separated and dried over anhydrous sodium sulfate.The precipitates collected by the filtration were added to thissolution, and a 4N dioxane solution (20 ml) of hydrochloric acid wasfurther added. The solvent was distilled off under reduced pressure, anddichloromethane (10 ml) and a 4N dioxane solution (10 ml) ofhydrochloric acid were added to the residue. The solvent was distilledoff again under reduced pressure. Ethyl acetate was added to the residueto collect precipitates by filtration, thereby obtaining the titlecompound (1.83 g) as a gray solid.

[0307]¹HNMR (DMSO-d₆) δ: 1.60-1.75(4H,m), 2.05-2.10(2H,m),3.49(1H,q,J=7.6 Hz), 4.27(4H,quintet,J=7.6 Hz), 7.17(1H,d,J=8.6 Hz),7.19(1H,s), 7.42(1H,d,J=8.6 Hz), 7.70(1H,s), 8.24(3H,br.s),8.85(1H,d,J=7.3 Hz), 11.91(1H,s) MS (ESI) m/z: 278(M+H)⁺.

Referential Example 36(±)-trans-N-tert-Butoxycarbonyl-1,2-cyclopentanediamine

[0308]

[0309] The title compound was obtained fromtrans-1,2-cyclopentanediamine (WO98/30574) in a similar manner toReferential Example 34.

[0310]¹H-NMR (CDCl₃) δ: 1.25-1.40(2H,m), 1.49(9H,s), 1.59-1.77(2H,m),1.92-2.08(1H,m), 2.10-2.17(1H,m), 2.98(1H,q,J=7.2 Hz), 3.48-3.53(1H,m),4.49(1H,br.s). MS (ESI) m/z: 201(M+H)⁺.

Referential Example 37(±)-trans-N-[(5-Methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride

[0311]

[0312] (±)-trans-N-tert-Butoxycarbonyl-1,2-cyclopentane-diamine (175 mg)was dissolved in N,N-dimethylformamide (3 ml), and to the solutionlithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate(purity: 90%, 258 mg), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimidehydrochloride (252 mg) and 1-hydroxybenzo-triazole monohydrate (60 mg)were added. The mixture was stirred at room temperature for 2 days. Thesolvent was distilled off under reduced pressure using a pump, anddichloromethane and a saturated solution of sodium hydrogencarbonatewere added to the residue to separate an organic layer. The resultantorganic layer was washed with saturated saline and dried over anhydroussodium sulfate, and the solvent was distilled off under reducedpressure. The residue was purified by medium-pressure flash columnchromatography on silica gel (dichloromethane:methanol=47:3). Theresultant pale yellow oil was dissolved in a saturated ethanol solution(5 ml) of hydrochloric acid, and the solution was stirred at roomtemperature for 1 hour. Ethyl acetate was then added, and the solventwas distilled off under reduced pressure. Ethyl acetate was added to theresidue to collect precipitate by filtration, thereby obtaining thetitle compound (120 mg) as a pale yellow solid.

[0313]¹H-NMR (DMSO-d₆) δ: 1.63-1.73(4H,m), 1.99-2.06(2H,m), 2.91(3H,s),3.09-3.14(1H,m), 3.25-3.70(4H,m), 4.27-4.32(1H,m), 4.42-4.46(1H,m),4.68-4.71(1H,m), 8.20-8.23(3H,m), 9.09(1H,d,J=8.3 Hz),11.82-12.01(1H,m). MS (ESI) m/z: 281(M+H)⁺.

Referential Example 38(±)-cis-N-(5-Chloro-1-phenylsulfonylindole-2-sulfonyl)-1,2-cyclopentanediamine

[0314]

[0315] cis-1,2-Cyclopentanediamine (WO98/30574) (348 mg) was dissolvedin dichloromethane (10 ml), and to the solution triethylamine (1 ml) and5-chloro-1-phenyl-sulfonylindole-2-sulfonyl chloride (390 mg) were addedat 0° C. with stirring. After 15 minutes and 1 hour,5-chloro-1-phenylsulfonylindole-2-sulfonyl chloride (156 mg) wasadditionally added. After stirring for 15 minutes,5-chloro-1-phenylsulfonylindole-2-sulfonyl chloride (78 mg) was furtheradded, and the mixture was stirred at room temperature for 2 hours.Water was added to the reaction mixture to separate an organic layer.The resultant organic layer was washed with a saturated solution ofsodium hydrogencarbonate and dried over anhydrous sodium sulfate. Theresidue was purified by flash column chromatography on silica gel(chloroform:methanol=23:2) to obtain the title compound (739 mg) as apale yellow solid.

[0316]¹H-NMR (CDCl₃) δ: 1.38-1.91(8H,m), 3.27-3.31(1H,m),3.41-3.45(1H,m), 7.42-7.50(4H,m), 7.58-7.61(2H,m), 8.11-8.15(3H,m). MS(ESI) m/z: 454(M+H)⁺.

Referential Example 39(±)-trans-N-tert-Butoxycarbonyl-1,2-cyclohexanediamine

[0317]

[0318] The title compound was obtained from(±)-trans-1,2-cyclohexanediamine in a similar manner to ReferentialExample 34.

[0319] mp 79-81° C. ¹H-NMR (CDCl₃) δ: 1.05-1.34(4H,m), 1.45(9H,s),1.68-1.75(2H,m), 1.92-2.02(2H,m), 2.32(1H,dt,J=10.3,3.9 Hz),3.08-3.20(1H,m), 4.50(1H,br.s). MS (FAB) m/z: 215(M+H)⁺.

Referential Example 40(±)-trans-N-[(5-Methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminetrifluoroacetate

[0320]

[0321] The title compound was-obtained from(±)-trans-N-tert-butoxycarbonyl-1,2-cyclohexanediamine in a similarmanner to Referential Example 37.

[0322]¹H-NMR (DMSO-d₆) δ: 1.10-1.80(7H,m), 1.95-2.05(1H,m), 2.97(3H,s),3.00-3.20(3H,m), 3.63(2H,br.s), 3.72-3.88(1H,m), 4.61(2H,br.s),7.98(3H,s), 8.89(1H,d,J=9.2 Hz). MS (FAB) m/z: 295(M+H)⁺.

Referential Example 41(±)-cis-N-tert-Butoxycarbonyl-1,2-cyclohexanediamine

[0323]

[0324] The title compound was obtained from cis-1,2-cyclohexanediaminein a similar manner to Referential Example 34.

[0325]¹H-NMR (CDCl₃) δ: 1.30-1.70(17H,m), 2.98-3.05(1H,m),3.60(1H,br.s), 4.98(1H,br.s). MS (FAB) m/z: 215(M+H)⁺.

Referential Example 42(±)-trans-N-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminetrifluoroacetate

[0326]

[0327] (±)-trans-N-tert-Butoxycarbonyl-1,2-cyclohexane-diamine (642 mg)was dissolved in N,N-dimethylformamide (20 ml), and to the solutionlithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate(795 mg), 1-hydroxybenzotriazole monohydrate (46 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.30 g)were added, and the mixture was stirred overnight at room temperature.After the reaction mixture was concentrated under reduced pressure, anddichloromethane and water were added to the residue, the organic layerwas taken out and dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (dichloromethane:methanol=100:3) toobtain a pale yellow foamy substance. This substance was dissolved indichloromethane (5 ml), and trifluoroacetic acid (30 ml) was added, andthe mixture was stirred at room temperature for 1 minute. The reactionmixture was concentrated under reduced-pressure to obtain the titlecompound (731 mg) as a pale brown foamy substance.

[0328]¹H-NMR (DMSO-d₆) δ: 1.10-1.80(7H,m), 1.95-2.05(1H,m), 2.97(3H,s),3.00-3.20(3H,m), 3.63(2H,br.s), 3.72-3.88(1H,m), 4.61(2H,br.s),7.98(3H,s), 8.89(1H,d,J=9.2 Hz) MS (FAB) m/z: 295(M+H)⁺.

Referential Example 43 Isolation of Optically Active Substances of(±)-cis-N¹-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[0329](±)-cis-N-[(5-Methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(900 mg) was dissolved in isopropyl alcohol (6 ml), and the solution waspurified in 11 portions by HPLC. As a column, CHIRALPAK AD (DaicelChemical Industries, Ltd.; 2.0 in diameter×25 cm) was used to conductelution at a flow rate of 6 ml/min using a solvent of hexane: isopropylalcohol:diethylamine=68:32:0.5. Fractions eluted after 24.8 minutes and33.4 minutes were separately collected and concentrated under reducedpressure to obtain Isomer A (320 mg) and Isomer B (390 mg) as brownamorphous substances.

[0330] Isomer A:

[0331]¹H-NMR (CDCl₃) δ: 1.30-1.90(8H,m), 2.51(3H,s), 2.82(2H,t,J=5.9Hz), 2.90-3.00(2H,m), 3.10-3.15(1H,m), 3.71(2H,s), 4.00-4.20(1H,m),7.55-7.75(1H,m). MS (FD⁺)m/z: 295(M+H)⁺.

[0332] Isomer B:

[0333]¹H-NMR (CDCl₃) δ: 1.30-1.90(8H,m), 2.51(3H,s), 2.82(2H,t,J=5.9Hz), 2.90-3.00(2H,m), 3.10-3.15(1H,m), 3.71(2H,s), 4.00-4.20(1H,m),7.55-7.75(1H,m). MS (FD⁺) m/z: 295(M+H)⁺.

[0334] In Referential Example 49, which will be described subsequently,Isomer B was identified as(1R,2S)-N¹-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine,and Isomer A as(1S,2R)-N¹-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine.

Referential Example 44 (1S,2S)-2-tert-Butoxycarbonylamino-1-cyclohexanol

[0335]

[0336] (1S,2S)-2-Amino-1-cyclohexanol (J. Med. Chem., 1998, Vol. 41, p.38) (0.83 g) was dissolved in dichloromethane (10 ml), and to thesolution di-tert-butyl dicarbonate (1.64 g) was added, and the mixturewas stirred at room temperature for 2 hours. The solvent was distilledoff under reduced pressure, and the resultant solids were recrystallizedfrom hexane:ethyl acetate=20:1 to obtain the title compound (1.33 g) ascolorless needle crystals.

[0337] mp: 103-105° C. [α]_(D) −5.48° (19.8° C., C=1.01, CHCl₃). ¹H-NMR(CDCl₃) δ: 1.05-1.50(4H,m), 1.45(9H,s), 1.65-1.75(2H,m),1.90-2.10(2H,m), 3.10-3.30(3H,m), 4.51(1H,br.s).

Referential Example 45(1S,2S)-1-tert-Butoxycarbonylamino-2-methanesulfonyloxy-cyclohexane

[0338]

[0339] (1S,2S)-2-tert-Butoxycarbonylamino-1-cyclohexanol (646 mg) wasdissolved in pyridine (4 ml), methane-sulfonyl chloride (378 mg) wasadded with ice cooling, and the mixture was stirred for 5 hours. Afterdiethyl ether was added to the reaction mixture and washed 5 times withwater, the resultant organic layer was dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure to obtainthe title compound (630 mg) as colorless crystals.

[0340] mp 123-124° C. [α]_(D)+7.16 ° (19.8° C., C=1.01, CHCl₃). ¹H-NMR(CDCl₃) δ: 1.20-1.40(3H,m), 1.44(9H,s), 1.55-1.70(2H,m),1.70-1.80(1H,m), 2.03-2.23(2H,m), 3.03(3H,s), 3.58(1H,br.s),4.44(1H,td,J=9.8,4.2 Hz), 4.67(1H,br.s)

Referential Example 46(1R,2S)-1-Azido-2-(tert-butoxycarbonylamino)cyclohexane

[0341]

[0342](1S,2S)-1-(tert-Butoxycarbonylamino)-2-methane-sulfonyloxycyclohexane(475 mg) was dissolved in N,N-dimethylformamide (6 ml), sodium azide(156 mg) was added, and the mixture was stirred for 2 hours at 60° C.and then for 24 hours at 80° C. After diethyl ether was added to thereaction mixture to conduct water washing twice, the resultant organiclayer was dried over anhydrous sodium sulfate. The solvent was distilledoff under reduced pressure, and the residue was purified by columnchromatography on silica gel (dichloromethane) to obtain the titlecompound (184 mg) as a colorless solid.

[0343] Mp 69-70° C. [α]_(D)−105.14° (19.8° C., C=1.01, CHCl₃). ¹H-NMR(CDCl₃) δ: 1.20-1.80(7H,m), 1.45(9H,s), 1.90-2.00(1H,m), 3.61(1H,br.s),3.95(1H,br.s), 4.70(1H,br.s). MS (FAB) m/z: 241(M+H)⁺.

Referential Example 47 (1S,2R)-N¹-tert-Butoxycarbonyl-1,2-cyclohexanediamine

[0344]

[0345] (1R,2S)-1-Azido-2-(tert-butoxycarbonylamino)-cyclohexane (174 mg)was dissolved in methanol (10 ml), and to the solution 10% palladium oncarbon (120 mg) was added to conduct catalytic reduction underatmospheric pressure. The catalyst was separated by filtration, and thefiltrate was concentrated to obtain a crude title compound (145 mg) as acolorless amorphous substance. This compound was used in the nextreaction without purifying it.

Referential Example 48(1S,2R)-N¹-tert-Butoxycarbonyl-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[0346]

[0347] Crude (1S,2R) -N¹-tert-butoxycarbonyl-1,2-cyclohexanediamine (145mg) was dissolved in N,N-dimethylformamide (3 ml), lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate (180mg), 1-hydroxybenzotriazole monohydrate (13 mg) and1-(3-dimethylaminopropyl)-3-ethylcarboduimide hydrochloride (770 mg)were added, and the mixture was stirred at room temperature for 22hours. After the reaction mixture was concentrated under reducedpressure, and dichloromethane and water were added to the residue toconduct liquid separation, the resultant organic layer was dried overanhydrous potassium carbonate. The solvent was distilled off underreduced pressure, and the residue was purified by column chromatographyon silica gel (dichloromethane: methanol=40:1) to obtain a pale yellowfoamy substance (126 mg).

[0348] [α]_(D)−19.96° (19.7° C., C=0.51, CHCl₃). ¹H-NMR (CDCl₃) δ:1.20-1.90(7H,m), 1.56(9H,s), 2.50(3H,s), 2.75-2.85(2H,m),2.85-2.95(2H,m), 3.71(2H,s), 3.88-4.00(1H,m), 4.22(1H,br.s),4.91(1H,br.s), 7.48(1H,br.s).

Referential Example 49(1R,2S)-N¹-[(5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[0349]

[0350](1S,2R)-N¹-tert-Butoxycarbonyl-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(120 mg) was dissolved in methanol (1 ml), 1N ethanolic hydrochloricacid (3 ml) was added, and the mixture was stirred at 50° C. for 2hours. The reaction mixture was concentrated under reduced pressure, anddiethyl ether was added to the residue to form powder. The powder iscollected by filtration to obtain the hydrochloride (106 mg) of thetitle compound as pale yellow powder.

[0351]¹H-NMR (DMSO-d₆) δ: 1.30-1.90(8H,m), 2.92(3H,s), 3.05-3.79(5H,m),4.24(1H,br.s), 4.34-4.79(2H,m), 7.85-8.20(3H,m), 8.30-8.49(1H,m),11.50-12.10(1H,m). MS (FAB) m/z: 295(M+H)⁺.

[0352] Dichloromethane and a saturated aqueous solution of sodiumhydrogencarbonate were added to a part of the hydrochloride of the titlecompound to conduct liquid separation. The resultant organic layer wasdried over anhydrous sodium sulfate, and the solvent was then distilledoff under reduced pressure. The residue was analyzed by HPLC(solvent:hexane:isopropyl alcohol:diethylamine=80:20:0.5; flow rate: 2ml/min) making use of CHIRALPAK AD (Daicel Chemical Industries, Ltd.;0.46 in diameter×25 cm). As a result, the title compound was eluted in9.5 minutes. Isomer A and Isomer B shown in Referential Example 43 wereeluted in 7.2 minutes and 9.5 minutes, respectively, under suchconditions. Therefore, Isomer B was identified as(1R,2S)-N¹-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine.

[0353]¹H-NMR (CDCl₃) δ: 1.30-1.90(8H,m), 2.51(3H,s), 2.82(2H,t,J=5.6Hz), 2.93(2H,t,J=5.6 Hz), 3.10-3.15(1H,m), 3.70(2H,s), 4.00-4.20(1H,m),7.63(1H,d,J=8.1 Hz).

Referential Example 50 (±)-trans-N-[(5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine hydrochloride

[0354]

[0355] The title compound was obtained from(±)-trans-N-tert-butoxycarbonyl-1,2-cyclohexanediamine in a similarmanner to Referential Example 37.

[0356]¹H-NMR (DMSO-d₆) δ: 1.10-2.17(8H,m), 2.92(3H,s), 3.00-3.93(6H,m),4.38-4.60(1H,m), 4.64-4.77(1H,m), 8.00-8.19(3H,m), 8.82-8.96(1H,m),11.95-11.30(1H,m). MS (FAB) m/z: 295(M+H)⁺.

Referential Example 51 (±)-cis-N-[(5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine hydrochloride

[0357]

[0358] The title compound was obtained from(±)-cis-N-tert-butoxycarbonyl-1,2-cyclohexanediamine in a similar mannerto Referential Example 37.

[0359]¹H-NMR (DMSO-d₆) δ: 1.30-1.90(8H,m), 2.92(3H,s), 3.05-3.79(5H,m),4.23(1H,br.s), 4.34-4.79(2H,m), 8.01-8.34(3H,m), 8.30-8.49(1H,m),11.90-12.30(1H,m). MS (FAB) m/z: 295(M+H)⁺.

Referential Example 52(±)-trans-N¹-(tert-Butoxycarbonyl)-N²-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine

[0360]

[0361] 5-Chloroindole-2-carboxylic acid (2.88 g), 1-hydroxybenzotriazolemonohydrate (2.08 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (2.95 g) were added to a solution of(±)-trans-N-tert-butoxycarbonyl-1,2-cyclohexanediamine (3.00 g) inN,N-dimethylformamide (10 ml) at room temperature. After stirring for 3days, the reaction mixture was concentrated under reduced pressure, anddichloromethane (30 ml), a saturated aqueous solution (150 ml) of sodiumhydrogencarbonate and water (150 ml). were added to the residue. Aftercollecting colorless precipitate formed was collected by filtration anddried to obtain the title compound (5.21 g) as a colorless solid.

[0362]¹H-NMR (DMSO-d₆) δ: 1.10-1.45(4H,m), 1.21(9H,s), 1.68(2H,d,J=8.1Hz), 1.86(2H,t,J=16.2 Hz), 3.22-3.42(1H,m), 3.69(1H,br.s),6.66(1H,d,J=8.5 Hz), 7.02(1H,s), 7.15(1H,dd,J=8.5,2.0 Hz),7.41(1H,d,J=8.5 Hz), 7.67(1H,d,J=2.0 Hz), 8.15(1H,d,J=8.1 Hz),11.73(1H,br.s). MS (ESI) m/z: 392(M+H)⁺.

Referential Example 53(±)-cis-N¹-(tert-Butoxycarbonyl)-N²-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine

[0363]

[0364] The title compound was obtained from(±)-cis-N-(tert-butoxycarbonyl)-1,2-cyclohexanediamine in a similarmanner to Referential Example 52.

[0365]¹H-NMR (DMSO-d₆) δ: 1.20-1.45(11H,m), 1.45-1.70(4H,m),1.70-1.85(2H,m), 3.76(1H,br.s), 4.08(1H,br.s), 6.64(1H,d,J=7.6 Hz),7.12(1H,s), 7.16(1H,dd,J=8.8,2.0 Hz), 7.43(1H,d,J=8.8 Hz),7.69(1H,d,J=2.0 Hz), 7.85(1H,d,J=6.9 Hz), 11.80(1H,br.s). MS (ESI) m/z:392(M+H)⁺.

Referential Example 54(±)-trans-N-[(5-Chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[0366]

[0367] A saturated ethanol solution (100 ml) of hydrochloric acid wasadded to a solution of(±)-trans-N¹-(tert-butoxycarbonyl)-N²-[(5-chloroindol-2-yl)-carbonyl]-1,2-cyclohexanediamine(5.18 g) in dichloromethane (100 ml) at room temperature. After stirringfor 2 days, the reaction mixture was concentrated under reducedpressure, diethyl ether (300 ml) was added to the resultant residue, andcolorless precipitate formed was collected by filtration and dried toobtain the title compound (4.30 g) as a colorless solid.

[0368]¹H-NMR (DMSO-d₆) δ: 1.20-1.36(2H,m), 1.36-1.50(2H,m),1.60(2H,br.s), 1.90(1H,d,J=13.0 Hz), 2.07(1H,d,J=13.7 Hz),3.06(1H,br.s), 3.83-3.96(1H,m), 7.15-7.24(2H,m), 7.45(1H,d,J=8.6 Hz),7.73(1H,s), 8.00(3H,br.s), 8.60(1H,d,J=8.3 Hz), 11.86(1H,s). MS (ESI)m/z: 292(M+H)⁺.

Referential Example 55(±)-cis-N-[(5-Chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine

[0369]

[0370] The title compound was obtained from(±)-cis-N¹-(tert-butoxycarbonyl)-N²-[(5-chloroindol-2-yl)-carbonyl]-1,2-cyclohexanediaminein a similar manner to Referential Example 54.

[0371]¹H-NMR (DMSO-d₆) δ: 1.30-1.50(2H,m), 1.55-1.95(6H,m),3.41(1H,br.s), 4.32(1H,br.s), 7.19(1H,dd,J=8.7,2.0 Hz), 7.33(1H,s),7.45(1H,d,J=8.7 Hz), 7.60-7.90(4H,m), 8.17(1H,d,J=7.1 Hz), 1.91(1H,s).MS (FAB) m/z: 292(M+H)⁺.

Referential Example 56(±)-cis-N¹-Benzyl-N²-tert-butoxycarbonyl-1,2-cyclohexanediamine

[0372]

[0373] (±)-cis-N-tert-Butoxycarbonyl-1,2-cyclohexanediamine (3.78 g) wasdissolved in acetonitrile (80 ml), and to the solution triethylamine(2.44 ml) and benzyl bromide (2.10 ml) were added, and the mixture wasstirred at room temperature for 13 hours. The solvent was distilled offunder reduced pressure, dichloromethane and water was added to theresidue to separate an organic layer. The organic layer was dried overanhydrous sodium sulfate and then concentrated under reduced pressure.The residue was purified by flash column chromatography on silica gel(hexane:ethyl acetate=1:1) to obtain the title compound (3.08 g) as apale orange oil.

[0374]¹H-NMR (CDCl₃) δ: 1.35-1.63(17H,m), 2.75-2.79(1H,m),3.71-3.83(3H,m), 5.17(1H,br.s), 7.22-7.33(5H,m). MS (FAB) m/z:305(M+H)⁺.

Referential Example 57(±)-cis-N¹-Benzyl-N²-tert-butoxycarbonyl-N¹-methyl-1,2-cyclohexanediamine

[0375]

[0376] (±)-cis-N¹-Benzyl-N²-tert-butoxycarbonyl-1,2-cyclohexanediamine(3.24 g) was dissolved in methanol (30 ml), and to the solution anaqueous solution (35%, 0.909 ml) of formaldehyde was added, and themixture was stirred at room temperature for 10 minutes. Sodiumcyanoborohydride (666 mg) was added to this mixture, and the resultantmixture was stirred at room temperature for 6 hours. Thereafter, asaturated aqueous solution of sodium hydrogencarbonate was added, andthe solvent was concentrated under reduced pressure. Dichloromethane wasadded to the residue to separate an organic layer. The organic layer wasdried over anhydrous sodium sulfate, and the solvent was distilled offunder reduced pressure. The residue was purified by flash columnchromatography on silica gel (hexane:ethyl acetate=3:1) to obtain thetitle compound (1.98 g) as a yellow oil.

[0377]¹H-NMR (CDCl₃) δ: 1.24-1.50(14H,m), 1.76-1.79(1H,m),1.93-1.98(1H,m), 2.15(3H,s), 2.16-2.21(1H,m), 2.30-2.35(1H,m),3.34(1H,d,J=13.4 Hz), 3.78(1H,d,J=13.4 Hz), 4.08(1H,br.s),5.09(1H,br.s), 7.20-7.32(5H,m). MS (ESI): 319(M+H)⁺.

Referential Example 58(±)-cis-N¹-tert-Butoxycarbonyl-N²-methyl-1,2-cyclohexane-diamine

[0378]

[0379](±)-cis-N¹-Benzyl-N²-tert-butoxycarbonyl-N¹-methyl-1,2-cyclohexanediamine(1.92 g) was added to methanol (50 ml), 10% palladium on carbon(containing 50% of water, 900 mg) was added, and the mixture was stirredfor 20 hours in a hydrogen atmosphere. After separating the catalyst byfiltration, the filtrate was concentrated to obtain the title compound(1.27 g) as a colorless oil.

[0380]¹H-NMR (CDCl₃) δ: 1.37-1.60(17H,m), 2.39(3H,s), 2.58-2.59(1H,m),3.48-3.49(1H,m), 3.72(1H,br.s), 5.10(1H,br.s). MS (ESI) m/z: 229(M+H)⁺.

Referential Example 59(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N¹-methyl-1,2-cyclohexanediaminetrifluoroacetate

[0381]

[0382] (±)-cis-N¹-tert-Butoxycarbonyl-N²-methyl-1,2-cyclohexanediamine(629 mg), 5-chloroindole-2-carboxylic acid (647 mg),1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (792 mg)and 1-hydroxy-benzotriazole monohydrate (186 mg) were dissolved inN,N-dimethylformamide (20 ml) and stirred at room temperature for 4days. The solvent was distilled off under reduced pressure by using apump, and dichloromethane and a saturated aqueous solution of sodiumhydrogencarbonate were added to the residue to separate an organiclayer. The organic layer was washed with an saturated aqueous solutionof sodium hydrogencarbonate and dried over anhydrous sodium sulfate, andthe solvent was distilled off under reduced pressure. The residue waspurified by flash column chromatography on silica gel (hexane:ethylacetate=1:1). The resultant pale yellow solid was dissolved in a mixedsolvent of dichloromethane (5 ml) and trifluoroacetic acid (5 ml) andstirred at room temperature for 1 hour. The solvent was distilled offunder reduced pressure, and dichloromethane and a saturated aqueoussolution of sodium hydrogencarbonate were added to separate an organiclayer. The organic layer was concentrated under reduced pressure, andethyl acetate was added to the residue. Precipitate formed was collectedby filtration to obtain the title compound (786 mg) as a pale yellowsolid.

[0383]¹H-NMR (CDCl₃) δ: 1.37-1.55(3H,m), 1.72-1.96(4H,m),2.09-2.19(1H,m), 3.23(3H,s), 3.76(1H,br.s), 4.34-4.39(1H,m),6.92(1H,d,J=1.7 Hz), 7.20(1H,dd,J=8.8,2.0 Hz), 7.46(1H,d,J=8.8 Hz),7.69(1H,d,J=2.0 Hz), 8.08(3H,br.s), 11.74(1H,br.s). MS (ESI) m/z:306(M+H)⁺.

Referential Example 60(±)-cis-N¹-(tert-Butoxycarbonyl)-N²-methyl-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[0384]

[0385] Lithium5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxylate (613mg) was suspended in dichloromethane (10 ml), to which a 1N ethanolsolution (3.0 ml) of hydrochloric acid was added, and the mixture wasstirred at room temperature for several minutes. The solvent wasdistilled off under reduced pressure, chloroform (15 ml),N,N-dimethylformamide (one drop) and thionyl chloride (5 ml) were addedto the residue, and the mixture was stirred at 60° C. for 4 hours. Thesolvent was distilled off under reduced pressure, and pyridine (10 ml)and dichloromethane (10 ml) were added to the residue, to which asolution (5 ml) of(±)-cis-N¹-(tert-butoxycarbonyl)-N²-methyl-1,2-cyclohexanediamine (455mg) in dichloromethane (5 ml) was added. After the mixture was stirredat room temperature for 2 hours, water was added to separate an organiclayer. After the resultant organic layer was washed with water andsaturated saline and dried over anhydrous sodium sulfate, the solventwas distilled off under reduced pressure. The residue was purified byflash column chromatography on silica gel(dichloromethane:methanol=47:3) to obtain the title compound (324 mg) asa pale brown solid.

[0386] MS (ESI) m/z: 409(M+H)⁺.

Referential Example 61 (±)-trans-1,2-Cycloheptanediol

[0387]

[0388] Cycloheptene (3.85 g) was added portionwise to 30% aqueoushydrogen peroxide (45 ml) and 88% formic acid (180 ml), and the mixturewas stirred at 40 to 50° C. for 1 hour and then at room temperature fora night. The solvent was distilled off under reduced pressure, and a 35%aqueous solution of sodium hydroxide was added to the residue toalkalify it. After this residue was stirred at 40 to 50° C. for 10minutes, ethyl acetate was added to conduct liquid separation. Theresultant water layer was extracted 4 times with ethyl acetate. Theresultant organic layers were collected and dried over anhydrous sodiumsulfate, and the solvent was distilled off under reduced pressure toobtain the title compound (4.56 g) as a colorless oil.

[0389]¹H-NMR (CDCl₃) δ: 1.44-1.56(6H,m), 1.63-1.70(2H,m),1.83-1.91(2H,m), 2.91(2H,br.s), 3.40-3.44(2H,m). MS (FAB) m/z:131(M+H)⁺.

Referential Example 62 (±)-trans-1,2-Cycloheptanediamine hydrochloride

[0390]

[0391] (±)-trans-1,2-Cycloheptanediol (4.56 g) was dissolved indichloromethane (35 ml), triethylamine (29 ml) was added, and themixture was cooled to −78° C. Methanesulfonyl chloride (8.13 ml) wasadded dropwise thereto. Since precipitate was formed to make itdifficult to stir, dichloromethane (10 ml) was slowly added, and themixture was stirred for 20 minutes at the same temperature and then for1.5 hours at 0° C. Water was added to the reaction mixture to conductliquid separation, and the resultant organic layer was washed with asaturated aqueous solution of sodium hydrogencarbonate and dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure to obtain a brown oil.

[0392] This oil was dissolved in N,N-dimethylformamide (90 ml), sodiumazide (13.65 g) was added, and the mixture was stirred at 65° C. for 18hours. Ether and water was added to the reaction mixture to conductliquid separation. The resultant ether layer was washed with a saturatedaqueous solution of sodium hydrogencarbonate and saturated saline anddried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure to obtain a yellow oil.

[0393] This oil was dissolved in ethanol (70 ml), 10% palladium oncarbon (containing 50% of water, 4 g) was added, and the mixture wasstirred for 4 days in a hydrogen (3.5 atm) atmosphere. After separatingthe palladium on carbon by filtration, a 1N ethanol solution (70 ml) ofhydrochloric acid was added to the filtrate, and the solvent wasdistilled off under reduced pressure. The residue was dissolved inmethanol, ethyl acetate was added, and the solvent was distilled offunder reduced pressure again. Precipitate formed was collected byfiltration to obtain the title compound (3.57 g) as a colorless solid.

[0394]¹H-NMR (DMSO) δ: 1.44(4H,br.s), 1.73-1.81(6H,m), 3.43(2H,br.s),8.63(6H,br.s). MS (ESI) m/z: 129(M+H)⁺.

Referential Example 63(±)-trans-N-[(5-Chloroindol-2-yl)carbonyl]-1,2-cycloheptanediamine

[0395]

[0396] The title compound was obtained from(±)-trans-1,2-cycloheptanediamine in a similar manner to ReferentialExample 30.

[0397]¹H-NMR (DMSO-d₆) δ: 1.49-1.52(4H,m), 1.72-1.91(6H,m),4.04-4.10(1H,m), 7.17-7.23(2H,m), 7.44(1H,d,J=8.8 Hz), 7.72(1H,d,J=2.0Hz), 7.96(2H,br.s), 8.75(1H,d,J=8.5 Hz), 11.89(1H,br.s) MS (ESI) m/z:306(M+H)⁺.

Referential Example 64 cis-1,2-Cycloheptanediol

[0398]

[0399] Cycloheptene (3.85 g) was dissolved in acetonitrile (45 ml) andwater (15 ml), and to the solution N-methylmorpholine N-oxide (5.15 g),microcapsulated osmium tetroxide (1 g, containing 10% osmium tetroxide)was added, and the mixture was stirred at 40 to 50° C. for 21 hours.Insoluble microcapsulated osmium tetroxide was removed by filtration,and the insoluble substance was washed with acetonitrile and thefiltrate was concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (hexane:ethylacetate=1:1) to obtain the title compound (4.77 g) as a colorless solid.

[0400]¹H-NMR (CDCl₃) δ: 1.34-1.84(10H,m), 2.31(2H,m), 3.86(2H,d,J=7.1Hz). MS (FAB) m/z: 131(M+H)⁺.

Referential Example 65 cis-1,2-Cycloheptanediazide

[0401]

[0402] Triethylamine (30 ml) was added to the solution ofcis-1,2-cycloheptanediol (4.76 g) in dichloromethane (50 ml), after theinterior of a vessel was purged with argon, the mixture was cooled to−78° C., and methanesulfonyl chloride (8.5 ml) was added dropwisethereto. The mixture was stirred for 1 hour at the same temperature andthen for 2 hours at 0° C. Water was added to the reaction mixture toconduct liquid separation, and the resultant organic layer was washedwith a saturated aqueous solution of sodium hydrogencarbonate and driedover anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was dissolved in N,N-dimethylformamide(90 ml), sodium azide (14.28 g) was added, and the mixture was stirredat 65° C. for 21 hours. Ether and water was added to the reactionmixture to conduct liquid separation. The resultant ether layer waswashed with a saturated aqueous solution of sodium hydrogencarbonate andsaturated saline and dried over anhydrous sodium sulfate. The solventwas distilled off under reduced pressure, and the residue was purifiedby flash column chromatography on silica gel (hexane:ethyl acetate=2:1)to obtain the title compound (3.57 g) as a colorless oil.

[0403]¹H-NMR (DMSO) δ: 1.46-1.80(8H,m), 1.89-1.98(2H,m),3.71(2H,dd,J=6.7,2.3 Hz).

Referential Example 66 cis-1,2-Cycloheptanediamine hydrochloride

[0404]

[0405] cis-1,2-Cycloheptanediazide (6.35 g) was dissolved in ethanol (75ml), to the solution 10% palladium on carbon (containing 50% of water,4.2 g) was added, and the mixture was stirred for 3 days in a hydrogen(3.5 atm) atmosphere. After separating the 10% palladium on carbon byfiltration, a 1N ethanol solution (70.5 ml) of hydrochloric acid wasadded to the filtrate, and the solvent was distilled off under reducedpressure. Ethyl acetate was added to the residue, and the solvent wasdistilled off under reduced pressure again. Precipitate formed wascollected by filtration and washed with ethyl acetate to obtain thetitle compound (5.28 g) as a colorless solid.

[0406]¹H-NMR (DMSO) δ: 1.44-1.68(6H,m), 1.79-1.93(4H,m),3.68(2H,dd,J=6.8,3.9 Hz), 8.62(6H,br.s). MS (ESI) m/z: 129(M+H)⁺.

Referential Example 67(±)-cis-N-[(5-Chloroindol-2-yl)carbonyl]-1,2-cycloheptanediamine

[0407]

[0408] The title compound was obtained from cis-1,2-cycloheptanediaminein a similar manner to Referential Example 30.

[0409] MS (ESI) m/z: 306(M+H)⁺.

Referential Example 68 cis-1,2-Cyclooctanediol

[0410]

[0411] Cyclooctene (4.41 g) was dissolved in acetonitrile (45 ml) andwater (15 ml), and to the solution N-methylmorpholine N-oxide (5.15 g)and microcapsulated osmium tetroxide (1 g, containing 10% osmiumtetroxide) were added, and the mixture was stirred at 40 to 50° C. for21 hours. Insoluble microcapsulated osmium tetroxide was removed byfiltration, and was washed with acetonitrile, and the filtrate wasconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (hexane:ethyl acetate=1:1) to obtainthe title compound (4.97 g) as a colorless solid.

[0412]¹H-NMR (CDCl₃) δ: 1.48-1.58(6H,m), 1.64-1.75(4H,m),1.86-1.96(2H,m), 2.28(2H,d,J=2.9 Hz), 3.90(2H,d,J=8.3 Hz). MS (FAB) m/z:145(M+H)⁺.

Referential Example 69 cis-1,2-Cyclooctanediazide

[0413]

[0414] cis-1,2-cyclooctanediol (4.82 g) was dissolved in dichloromethane(60 ml), and to the solution triethylamine (27.7 ml) was added. Afterthe interior of a vessel was purged with argon, the mixture was cooledto −78° C., and methanesulfonyl chloride (7.7 ml, 100 mmol) was addeddropwise thereto. The mixture was stirred for 1 hour at the sametemperature and then for 1 hour at 0° C. Water was then added to thereaction mixture to conduct liquid separation, and the resultant organiclayer was washed with water, 0.5N hydrochloric acid, water and asaturated aqueous solution of sodium hydrogencarbonate and dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, and the residue was dissolved in N,N-dimethylformamide (80ml), and to the solution sodium azide (13.0 g) was added, and themixture was stirred at 65° C. for 19 hours. Ether and water was added tothe reaction mixture to conduct liquid separation. The resultant etherlayer was washed with a saturated aqueous solution of sodiumhydrogencarbonate and saturated saline and dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, and theresidue was purified by flash column chromatography on silica gel(hexane:ethyl acetate=6:1) to obtain the title compound (4.85 g) as acolorless oil.

[0415]¹H-NMR (CDCl₃) δ: 1.49-1.64(6H,m), 1.67-1.78(2H,m),1.81-1.97(4H,m), 3.74-3.76(2H,m).

Referential Example 70 cis-1,2-Cyclooctanediamine hydrochloride

[0416]

[0417] cis-1,2-Cyclooctanediazide (4.85 g) was dissolved in ethanol (55ml), to the solution 10% palladium on carbon (containing 50% of water,3.0 g) was added, and the mixture was stirred for 21 hours in a hydrogen(4.5 atm) atmosphere. After separating the catalyst by filtration, a 1Nethanol solution (50 ml) of hydrochloric acid was added to the filtrate,and the solvent was distilled off under reduced pressure. Ethyl acetatewas added to the residue, and precipitate formed was collected byfiltration to obtain the title compound (4.14 g) as a pale yellow solid.

[0418]¹H-NMR (DMSO) δ: 1.51(6H,br.s), 1.69(2H,br.s), 1.79-1.99(4H,m),3.68-3.70(2H,m), 8.66(6H,br.s). MS (ESI) m/z: 143(M+H)⁺.

Referential Example 71(±)-cis-N-[(5-Chloroindol-2-yl)carbonyl]-1,2-cyclooctanediamine

[0419]

[0420] The title compound was obtained from cis-1,2-cyclooctanediaminein a similar manner to Referential Example 30.

[0421] MS (ESI) m/z: 320(M+H)⁺.

Referential Example 72N¹-tert-Butoxycarbonyl-N²-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-ethylenediamine

[0422]

[0423] tert-Butyl N-(2-aminoethyl)carbamate (1.0 g) was dissolved inN,N-dimethylformamide, and to the solution lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxylate(purity: 90%, 1.13 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (1.79 g) and 1-hydroxybenzotriazole monohydrate (422 mg)were added, and the mixture was stirred at room temperature for 23hours. The solvent was distilled off under reduced pressure using avacuum pump, and dichloromethane and a saturated solution of sodiumhydrogencarbonate were added to the residue to conduct liquidseparation. The resultant water layer was extracted withdichloromethane, the resultant organic layers were collected and driedover anhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by flash columnchromatography on silica gel (dichloromethane:methanol=91:9) to obtainthe title compound (1.26 g) as a pale yellow solid.

[0424]¹H-NMR (CDCl₃) δ: 1.43(9H,s), 2.51(3H,m), 2.81-2.84(2H,m),2.91-2.95(2H,m), 3.35-3.40(2H,m), 3.53-3.57(2H,m), 3.71(2H,s),5.30(1H,br.s), 7.47(1H,br.s). MS (FAB) m/z: 341(M+H)⁺.

Referential Example 73N¹-tert-Butoxycarbonyl-N²-[(1-phenylsulfonyl-5-chloroindol-2-yl)sulfonyl]-1,2-ethylenediamine

[0425]

[0426] tert-Butyl N-(2-aminoethyl)carbamate (1.0 g) was dissolved indichloromethane, to the solution5-chloro-1-phenylsulfonyl-indole-2-sulfonyl chloride (2.44 g) andtriethylamine (1.73 ml) were added, and the mixture was stirredovernight at room temperature. Water was added to the reaction mixtureto conduct liquid separation, and the resultant water layer wasextracted with dichloromethane. The resultant organic layers werecollected and dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (hexane:ethyl acetate=4:1→3:2) toobtain the title compound (2.83 g) as a colorless solid.

[0427]¹H-NMR (CDCl₃) δ: 1.43(9H,s), 3.17-3.21(2H,m), 3.28-3.31(2H,m),4.89(1H,br.s), 5.97-6.00(1H,m), 7.42-7.51(4H,m), 7.59-7.65(2H,m),8.11-8.16(3H,m). MS (FAB) m/z: 514(M+H)⁺.

Referential Example 74N¹-tert-Butoxycarbonyl-N¹-methyl-1,2-ethylenediamine

[0428]

[0429] Synthesis was performed in accordance with literature (J. Med.Chem., 1990, Vol. 33, p. 97). N-methyl-1,2-ethylenediamine (5.57 ml) wasdissolved in dichloromethane (80 ml), and a solution of di-tert-butyldicarbonate (4.37 g) in dichloromethane (20 ml) was added at 0° C. Themixture was stirred overnight at room temperature. Saturated saline wasadded to the reaction mixture to conduct liquid separation. Theresultant organic layer was washed with saturated saline and dried overanhydrous sodium sulfate. The thus-obtained product was purified bycolumn chromatography on silica gel (chloroform:methanol=9:1→4:1) toobtain the title compound (2.96 g) as a pale yellow oil from an initialeluate.

[0430]¹H-NMR (DMSO-d₆) δ: 1.37(9H,s), 2.63(2H,t,J=6.7 Hz), 2.77(3H,s),3.12(2H,t,J=6.7 Hz). MS (ESI) m/z: 175(M+H)⁺.

[0431] Further, N¹-tert-butoxycarbonyl-N²-methyl-1,2-ethylenediamine(339 mg) was obtained as a pale yellow oil from the next eluate.

[0432]¹H-NMR (DMSO-d₆) δ: 1.36(9H,s), 2.24(3H,s), 2.46(2H,t,J=6.5 Hz),2.97(2H,q,J=6.5 Hz), 6.68(1H,br.s). MS (ESI) m/z: 175(M+H)⁺.

Referential Example 75N¹-Methyl-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-ethylenediaminehydrochloride

[0433]

[0434] N¹-tert-Butoxycarbonyl-N¹-methyl-1,2-ethylene-diamine (1.05 g)was dissolved in N,N-dimethylformamide (30 ml), to which lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate (157mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (181mg) and 1-hydroxybenzotriazole monohydrate (42 mg) were added, and themixture was stirred overnight at room temperature. The solvent wasdistilled off under reduced pressure using a vacuum pump, anddichloromethane and a saturated solution of sodium hydrogencarbonatewere added to the residue to conduct liquid separation. The resultantwater layer was extracted with dichloromethane, the resultant organiclayers were collected and dried over anhydrous sodium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by flash column chromatography on silica gel(dichloromethane:methanol=23:2), and the resultant compound wasdissolved in a small amount of dichloromethane, to which a saturatedethanol solution (8 ml) of hydrochloric acid was added, and the mixturewas stirred at room temperature for 1 hour. After the solvent wasdistilled off under reduced pressure, ethyl acetate was added, andprecipitate formed was collected by filtration to obtain the titlecompound (697 mg) as a pale yellow solid.

[0435]¹H-NMR (DMSO-d₆) δ: 2.54(3H,s), 2.89(3H,s), 3.02-3.28(4H,m),3.43-3.74(4H,brm), 4.45(1H,br.s), 4.66(1H,br.s), 8.79(2H,br.s),9.04(1H,t,J=5.9 Hz), 11.88(1H,br.s). MS (FAB) m/z: 255(M+H)⁺.

Referential Example 76N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-methyl-1,2-ethylenediaminehydrochloride

[0436]

[0437] N¹-tert-Butoxycarbonyl-N¹-methyl-1, 2-ethylene-diamine (348 mg)was dissolved in N,N-dimethylformamide (5 ml), to which5-chloroindole-2-carboxylic acid (391 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (575 mg) and1-hydroxybenzotriazole monohydrate (135 mg) were added, and the mixturewas stirred at room temperature for 3 days. The solvent was distilledoff under reduced pressure, and dichloromethane and a saturated solutionof sodium hydrogencarbonate were added to the residue to conduct liquidseparation. The resultant organic layer was dried over anhydrous sodiumsulfate, and the solvent was distilled off under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(dichloromethane:methanol=47:3), and the resultant pale yellow solid wasdissolved in dichloromethane (10 ml) and methanol (10 ml), to which asaturated ethanol solution (10 ml) of hydrochloric acid was added, andthe mixture was stirred at room temperature for 1 hour. After thesolvent was distilled off under reduced pressure, ethyl acetate wasadded, and precipitate formed was collected by filtration to obtain thetitle compound (288 mg) as a pale yellow solid.

[0438]¹H-NMR (DMSO-d₆) δ: 2.59(3H,t,J=5.4 Hz), 3.11(2H,quint,J=5.9 Hz),3.61(2H,q,J=5.9 Hz), 7.19(1H,dd,J=8.8,2.2 Hz), 7.22(1H,d,J=1.2 Hz),7.44(1H,d,J=8.8 Hz), 7.71(1H,d,J=2.2 Hz), 9.00(1H,t,J=5.9 Hz),9.03(2H,br.s), 11.89(1H,br.s). MS (ESI) m/z: 252(M+H)⁺.

Referential Example 77N¹-tert-Butoxycarbonyl-N¹,N²-dimethyl-1,2-ethylene-diamine

[0439]

[0440] N,N′-Dimethyl-1,2-ethylenediamine (1.07 ml) was dissolved indichloromethane, and to the solution di-tert-butyl dicarbonate (2.18 g)was added at room temperature, and the mixture was stirred overnight.The solvent was distilled off under reduced pressure, and the residuewas purified by column chromatography on silica gel(dichloromethane:methanol=4:1) to obtain the title compound (678 mg) asa yellow oil.

[0441]¹H-NMR (CDCl₃) δ: 1.46(9H,s), 2.48(3H,br.s), 2.78(2H,br.s),2.89(3H,s), 3.37(2H,br.s). MS (ESI) m/z: 189(M+H)⁺.

Referential Example 78 4-(2-Pyridyl)benzoic acid

[0442]

[0443] 2-(p-Toluyl)pyridine (17.2 g) was suspended in water (200 ml),and to the suspension potassium permanganate (21.0 g) was added. Themixture was heated under reflux for 18 hours. After the reaction mixturewas allowed to cool, and insoluble matter was removed by filtration,dichloromethane was added to the filtrate, and the resultant water layerwas separated and acidified with 2N hydrochloric acid. The solution wasconcentrated, and precipitate was collected by filtration to obtain thetitle compound (7.07 g) as a white solid.

[0444]¹H-NMR (DMSO-d₆) δ: 7.60(1H,t,J=5.9 Hz), 8.08(2H,d,J=7.8 Hz),8.17(2H,m), 8.21(2H,d,J=7.8 Hz), 8.78(1H,d,J=4.9 Hz). MS (EI) m/z:199(M⁺).

Referential Example 79 Thiazolo[4,5-c]pyridine

[0445]

[0446] 3-(tert-Butoxycarbonylamino)-4-mercaptopyridine (Japanese PatentApplication Laid-Open No. 321691/1992) (9.20 g) was dissolved in formicacid (60 ml) and heated under reflux for 4 hours. The reaction mixturewas concentrated under reduced pressure, and a 4N aqueous solution (100ml) of potassium hydroxide and ether were added to the residue toconduct liquid separation. The resultant organic layer was dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. Ether was added to the residue, and solids depositedwere collected by filtration to obtain the title compound (3.97 g) as acolorless solid.

[0447]¹H-NMR (CDCl₃) δ: 7.93(1H,d,J=5.4 Hz), 8.60(1H,d,J=5.4 Hz);9.07(1H,s), 9.46(1H,s).

Referential Example 805-Methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine

[0448]

[0449] The title compound was obtained from thiazolo-[4,5-c]pyridine ina similar manner to Referential Example 4.

[0450]¹H-NMR (CDCl₃) δ: 2.52(3H,s), 2.77(2H,t,J=5.4 Hz),2.92-3.00(2H,m), 3.69(2H,t,J=2.0 Hz), 8.61(1H,s). MS (FAB) m/z:155(M+H)⁺.

Referential Example 81 Lithium5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]-pyridine-2-carboxylate

[0451]

[0452] The title compound was obtained from5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine in a similar mannerto Referential Example 5.

[0453]¹H-NMR (DMSO-d₆) δ: 2.38(3H,s), 2.64(2H,br.s), 2.80(2H,br.s),3.44(2H,br.s). MS (FD) m/z: 199(M+H)⁺.

Referential Example 82 6-Methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine

[0454]

[0455] A 35% aqueous solution (6 ml) of formaldehyde was added to3-[(2-amino)ethyl]thiophene (Arkiv för kemi, 1971, Vol. 32, p. 217)(4.50 g) with ice cooling, and the mixture was heated and stirred at 90°C. 3 hours. The reaction mixture was cooled back to room temperature andextracted with benzene. The resultant organic layer was washed withwater and then dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure, and 7N hydrochloric acid was addedto the residue to stir the mixture overnight at room temperature. Thereaction mixture was concentrated under reduced pressure, and a 3Naqueous solution (100 ml) of sodium hydroxide and dichloromethane wereadded to conduct liquid separation. After the resultant organic layerwas dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure, the residue was dissolved indichloromethane (200 ml), and a 35% aqueous solution (2 ml) offormaldehyde, acetic acid (2 ml) and sodium triacetoxyborohydride (11.24g) were added to stir the mixture at room temperature for 1 hour. A 3Naqueous solution (100 ml) of sodium hydroxide was added to the reactionmixture, and the resultant organic layer was separated and then driedover anhydrous magnesium sulfate. The solvent was distilled off underreduced pressure, and the residue was distilled under reduced pressure(0.3 mmHg, 45 to 47° C.) to obtain the title compound (1.82 g) as acolorless oil.

[0456]¹H-NMR (CDCl₃) δ: 2.49(3H,s), 2.70-2.80(4H,m), 3.64(2H,s),6.78(1H,d,J=4.9 Hz), 7.09(1H,d,J=4.9 Hz). MS (FAB) m/z: 154(M+H)⁺.

Referential Example 83 Lithium6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]-pyridine-2-carboxylate

[0457]

[0458] The title compound was obtained from6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine in a similar manner toReferential Example 5.

[0459]¹H-NMR (DMSO-d₆) δ: 2.48-2.70(4H,m), 3.30-3.50(3H,m), 3.61(1H,s),7.01(1H,s). MS (FD) m/z: 198(M+H)⁺.

Referential Example 842-Chloro-5-(N,N-dimethylamino)-4,5,6,7-tetrahydrobenzo-[d]thiazole

[0460]

[0461] 2-Chloro-5-oxo-4,5,6,7-tetrahydrobenzo[d]thiazole (Helv. Cim.Acta., 1994, Vol. 77, p. 1256) (2.0 g) was dissolved in methanol (100ml), and ammonium acetate (8.2 g) and sodium cyanoborohydride (4.0 g)were added to heat the mixture under reflux. After 20 hours, thereaction was stopped, hydrochloric acid was added to decompose excessivesodium cyanoborohydride before the solvent was distilled off underreduced pressure. The residue was alkalified with a 1N solution ofsodium hydroxide and then extracted with dichloromethane. The resultantorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure to obtain a pale yellowoil. This oil was dissolved in methanol (50 ml), and an aqueous solution(4.29 g) of formaldehyde and sodium cyanoborohydride (3.49 g) were addedto stir the mixture at room temperature for 12 hours. The solvent wasdistilled off under reduced pressure, and methylene chloride was addedto the residue, the organic layer was washed with a saturated aqueoussolution of sodium hydrogencarbonate and dried over anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure, and theresidue was purified by column chromatography on silica gel(dichloromethane:methanol=10:1) to obtain the title compound (740 mg) asa pale yellow oil.

[0462]¹H-NMR (CDCl₃) δ: 1.71-1.78(1H,m), 2.10-2.19(1H,m), 2.35(6H,s),2.66-2.94(5H,m). MS (FAB) m/z: 217(M+H)⁺.

Referential Example 85 Lithium[5-(N,N-dimethylamino)-4,5,6,7-tetrahydrobenzo-[d]thiazol-2-yl]carboxylate

[0463]

[0464] After2-chloro-5-(N,N-dimethylamino)-4,5,6,7-tetrahydrobenzo[d]thiazole (750mg) was dissolved in ether (15 ml), and the solution was cooled to −78°C., 1.5N t-butyllithium (3.5 ml) was added, and the mixture was stirred.After 20 minutes, carbon dioxide was bubbled, and the bubbling wasstopped after about 15 minutes. The reaction mixture was warmed to roomtemperature and concentrated under reduced pressure to obtain the titlecompound as a pale yellow amorphous substance.

[0465]¹H-NMR (DMSO-d₆) δ: 1.75-1.78(1H,m), 1.98-2.07(1H,m), 2.50(6H,s),2.64-2.88(5H,m).

Referential Example 86 4-(Morpholinomethyl)thiazole

[0466]

[0467] 4-Methylthiazole (1.98 g), N-bromosuccinimide (3.56 g) andα,α′-azobisisobutyronitrile (164 mg) were dissolved in carbontetrachloride (200 ml), and the solution was heated under reflux for 2hours. After completion of the reaction, insoluble matter was removed byfiltration, N,N-dimethylformamide (20 ml) was added to the filtrate, andcarbon tetrachloride was distilled off under reduced pressure to obtainan N,N-dimethylformamide solution (about 20 ml) of4-(bromomethyl)thiazole. Morpholine (871 μl), triethylamine (2.79 ml)and N,N-dimethylformamide (10 ml) were successively added to thisN,N-dimethyl-formamide solution (about 10 ml) of4-(bromomethyl)-thiazole, and the mixture was stirred overnight at roomtemperature. The solvent was distilled off under reduced pressure,dichloromethane and a saturated aqueous solution of sodium hydrogencarbonate were added to the residue and an organic layer was separated.The organic layer was dried over anhydrous sodium sulfate. The solventwas distilled off under reduced pressure, and the residue was purifiedby column chromatography on silica gel (methanol:dichloromethane=1:19)to obtain the title compound (700 mg) as a yellow oil.

[0468]¹H-NMR (CDCl₃) δ: 2.45-2.60(4H,br), 3.65-3.90(6H,br), 7.21(1H,s),8.79(1H,s). MS (ESI) m/z: 185(M+H)⁺.

Referential Example 87 5-[(N,N-Dimethylamino)methyl]thiazole

[0469]

[0470] An N,N-dimethylformamide solution of 5-(bromo-methyl)thiazole wasprepared by using 5-methylthiazole (5.00 g), N-bromosuccinimide (8.97 g)and α,α′-azobisisobutyronitrile (414 mg) in a similar manner toReferential Example 86, and morpholine (2.20 ml) and triethylamine (7.02ml) were reacted with this solution to obtain the title compound (1.76g) as a yellow oil.

[0471] 1H-NMR (CDCl₃) δ: 2.27(6H,s), 3.68(2H,s), 7.70(1H,s), 8.75(1H,s).MS (ESI) m/z: 143(M+H)⁺.

Referential Example 88 Lithium4-(morpholinomethyl)thiazole-2-carboxylate

[0472]

[0473] 4-(Morpholinomethyl)thiazole (640 mg) was dissolved in diethylether (5 ml) in an argon atmosphere, and n-butyllithium (1.54N hexanesolution, 2.50 ml) was added dropwise at −78° C. The reaction mixturewas stirred for 10 minutes under ice cooling, and cooled again to −78°C. After blowing carbon dioxide into the reaction mixture for 20minutes, it was heated to room temperature. The reaction mixture wasconcentrated under reduced pressure to obtain the title compound (873mg) as crude yellow powder.

[0474]¹H-NMR (DMSO-d₆) δ: 2.40(4H,br.s), 3.50-3.70(6H,m), 7.34(1H,s).

Referential Example 89 Lithium5-[(N,N-dimethylamino)methyl]thiazole-2-carboxylate

[0475]

[0476] The title compound (2.34 g) was obtained as violet powder from5-[(N,N-dimethylamino)methyl]thiazole (1.81 g) in a similar manner toReferential Example 5.

[0477]¹H-NMR (DMSO-d₆) δ: 2.14(6H,br.s), 3.56(2H,br.s), 7.51(1H,s).

Referential Example 902-Amino-5-tert-butoxycarbonyl-4,6-dihydro-5H-pyrrolo-[3,4-d]thiazole

[0478]

[0479] 1-tert-Butoxycarbonyl-3-pyrrolidone (1.58 g) was dissolved incyclohexane (10 ml), p-toluenesulfonic acid monohydrate (8.12 mg) andpyrrolidine (607 mg) were added, and the mixture was heated under refluxfor 1.5 hours while dewatering by a Dean-Stark trap. After a supernatantwas taken out and concentrated under reduced pressure, the residue wasdissolved in methanol (5 ml), and sulfur powder (274 mg) was added. Themixture was stirred for 15 minutes under ice cooling. A methanolsolution (2 ml) of cyanamide (377 mg) was slowly added dropwise to thereaction mixture, and the mixture was stirred overnight at roomtemperature. Then the mixture was heated under reflux for 2 hours, thereaction mixture was concentrated, and dichloromethane and a saturatedaqueous solution of sodium hydrogen carbonate were added. The resultantorganic layer was dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (methanol:dichloromethane=1:39) toobtain the title compound (248 mg) as a yellow oil.

[0480]¹H-NMR (CDCl₃) δ: 1.50(9H,s), 4.34-4.37(1H,m), 4.40-4.45(1H,m),4.49-4.55(2H,m), 4.99(2H,m).

Referential Example 912-Bromo-5-tert-butoxycarbonyl-4,6-dihydro-5H-pyrrolo-[3,4-d]thiazole

[0481]

[0482] Copper(II) bromide (445 mg) was suspended inN,N-dimethylformamide, and tert-butyl nitrite (256 mg) was addeddropwise at room temperature. After an N,N-dimethylformamide solution (1ml) of2-amino-5-tert-butoxycarbonyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole (400mg) was added under ice cooling, the reaction mixture was heated andstirred at 60° C. for 1.5 hours. Diethyl ether and saturated saline wereadded to the reaction mixture, and the resultant organic layer was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by column chromatography on silicagel (ethyl acetate:hexane=1:4) to obtain the title compound (174 mg) aspale yellow powder.

[0483]¹H-NMR (CDCl₃) δ: 1.51(9H,s), 4.52-4.55(1H,m), 4.57-4.67(3H,m) MS(FAB) m/z: 305(M+H)⁺.

Referential Example 925-(Benzenesulfonyl)-4,6-dihydro-5H-pyrrolo[3,4-d]-thiazole

[0484]

[0485] 1) 4,5-Dimethylthiazole (5.00 g), N-bromo-succinimide (15.7 g)and α,α′-azobisisobutyronitrile (362 mg) were dissolved indichloroethane (500 ml) at room temperature, and the solution was heatedunder reflux for 1 hour. The solvent was distilled off, and the residuewas purified by column chromatography on silica gel (hexane:diethylether=1:4) to obtain 4,5-bis(bromomethyl)thiazole (5.24 g) as a paleyellow oil.

[0486]¹H-NMR (CDCl₃) δ: 4.64(2H,s), 4.74(2H,s), 8.75(1H,s).

[0487] 2) Benzenesulfonamide (638 mg) and 4,5-bis(bromo-methyl)thiazole(1.10 g) were dissolved in dimethylformamide (10 ml), 60% sodium hydridein oil (357 mg) was added at a time, and the mixture was stirred at roomtemperature for 3 hours. Water and dichloromethane were added to conductliquid separation. After the resultant oil layer was dried overanhydrous sodium sulfate, the solvent was distilled off, and the residuewas purified by column chromatography on silica gel(dichloromethane:ethylacetate=9:1) to obtain the title compound (137 mg)as colorless powder.

[0488]¹H-NMR (CDCl₃) δ: 4.60-4.63(2H,m), 4.70-4.73(2H,m),7.52-7.64(3H,m), 7.88-7.92(2H,m), 8.71(1H,s). MS (FAB) m/z: 267(M+H)⁺.

Referential Example 93 4,6-Dihydro-5H-pyrrolo[3,4-d]thiazolehydrobromide

[0489]

[0490] A mixture of5-(benzenesulfonyl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole (800 mg),phenol (800 μl) and 47% hydrobromic acid (5.00 ml) was heated underreflux for 2 hours. After the reaction mixture was cooled to roomtemperature, ethyl acetate and water were added to conduct liquidseparation. The-resultant water layer was concentrated under reducedpressure. Ethyl acetate was added to the residue, colorless powderdeposited was collected by filtration to obtain the title compound (521mg).

[0491]¹H-NMR (DMSO-d₆) δ: 4.42(2H,br.s), 4.56(2H,br.s), 9.14(1H,s). MS(FAB) m/z: 127(M+H)⁺.

Referential Example 94 5-Methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole

[0492]

[0493] The title compound was obtained from4,6-dihydro-5H-pyrrolo[3,4-d]thiazole hydrobromide and formalin in asimilar manner to Referential Example 12.

[0494]¹H-NMR (CDCl₃) δ: 2.67(3H,s), 3.95-3.99(2H,m), 4.01-4.05(2H,m),8.69(1H,s). MS (ESI) m/z: 141(M+H)⁺.

Referential Example 95 Lithium5-methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-2-carboxylate

[0495]

[0496] 5-Methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole (771 mg) wasdissolved in tetrahydrofuran (10 ml) in an argon atmosphere, and thesolution was cooled to −78° C. tert-Butyllithium (1.54N pentanesolution, 3.93 ml) was added dropwise to this reaction mixture. Thereaction mixture was stirred for 1 hour under ice cooling, and cooledagain to −78° C. After blowing carbon dioxide into the reaction mixturefor 20 minutes, it was heated to room temperature. The reaction mixturewas concentrated under reduced pressure to obtain the title compound(1.08 g) as crude brown powder.

[0497]¹H-NMR (DMSO-d₆) δ: 2.52(3H,s), 3.73(2H,t,J=3.2 Hz),3.87(2H,t,J=3.2 Hz).

Referential Example 962-Bromo-5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine

[0498]

[0499] 2-Bromo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinetrifluoroacetate (5.00 g) was suspended in dichloromethane (200 ml), andto the suspension triethylamine (4.16 ml) was added, and the mixture wasstirred at room temperature into a solution. Acetic acid (2.55 ml) andacetone (17 ml) were added to the reaction mixture, and the mixture wasstirred at room temperature for 2 minutes. Sodium triacetoxyborohydride(19.1 g) was added to the reaction mixture, and the resultant mixturewas stirred at room temperature for 5 hours. A 3N aqueous solution (200ml) of sodium hydroxide was added to the reaction mixture to separate anorganic layer. After the organic layer was dried over anhydrous sodiumsulfate, the solvent was distilled off under reduced pressure. Theresidue was purified by column chromatography on silica gel(dichloromethane:methanol=100:1) to obtain the title compound (3.45 g)as a yellow oil.

[0500]¹H-NMR (CDCl₃) δ: 1.13(6H,d,J=6.6 Hz), 2.86(4H,s),2.92-3.01(1H,m), 3.70(2H,s). MS (FAB) m/z: 261(M⁺).

Referential Example 97 Lithium5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxylate

[0501]

[0502] The title compound was obtained from2-bromo-5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine in asimilar manner to Referential Example 13.

[0503]¹H-NMR (DMSO-d₆) δ: 0.90-1.20(6H,m), 2.60-3.03(5H,m),3.58-4.00(2H,m).

Referential Example 98 Lithium5-tert-butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carboxylate

[0504]

[0505] The title compound was obtained from2-bromo-5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridinein a similar manner to Referential Example 13.

[0506]¹H-NMR (DMSO-d₆) δ: 1.42(9H,s), 2.69-2.77(2H,m), 3.60-3.68(2H,m),4.51-4.58(2H,m). MS (FAB) m/z: 285(M+H)⁺.

Referential Example 99 Methyl2-bromo-5-methoxycarbonylthiazole-4-acetate

[0507]

[0508] Copper(II) chloride (26.8 g) was added to a solution oftert-butyl nitrite (15.5 g) in acetonitrile (500 ml) at a time under icecooling. A solution of methyl2-amino-5-methoxycarbonylthiazole-4-acetate (Yakugaku Zasshi, 1966, Vol.86, p. 300) (23.0 g) in acetonitrile (500 ml) was added dropwise over 45minutes, and the mixture was stirred for 1 hour under ice cooling andfor 30 minutes at room temperature. The solvent was concentrated, and10% hydrochloric acid and diethyl ether were added to the residue toseparate an organic layer. The organic layer was dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure,and the residue was purified by column chromatography on silica gel(ethyl acetate:hexane=1:4) to obtain the title compound (25.9 g) as ayellow solid.

[0509]¹H-NMR (CDCl₃) δ: 3.73(3H,s), 3.87(3H,s), 4.21(2H,s).

Referential Example 100 4-(2-Hydroxyethyl)-5-hydroxymethylthiazole

[0510]

[0511] A solution of methyl 2-bromo-5-methoxycarbonyl-thiazole-4-acetate(23.4 g) in tetrahydrofuran (500 ml) was added dropwise over 1 hour to asuspension of lithium aluminum hydride (9.03 g) in tetrahydrofuran (500ml) under ice cooling. After stirring for additional 1 hour under icecooling, water (9 ml), a 35% aqueous solution (9 ml) of sodium hydroxideand water (27 ml) were successively added, and the mixture was stirredat room temperature for 1 hour. After anhydrous magnesium sulfate wasadded to the reaction mixture, and the resultant mixture was stirred,insoluble matter was removed by filtration with Celite, and the filtratewas concentrated. The residue was purified by column chromatography onsilica gel (methanol:dichloromethane=7:93) to obtain the title compound(8.64 g) as a yellow oil.

[0512]¹H-NMR (CDCl₃) δ: 3.01(2H,t,J=5.5 Hz), 3.30(1H,br.s),3.57(1H,br.s), 3.90(2H,br.s), 4.75(2H,br.s), 8.66(1H,s). MS (ESI) m/z:160(M+H)⁺.

Referential Example 1014-(2-Methanesulfonyloxyethyl)-5-(methanesulfonyloxy-methyl)thiazole

[0513]

[0514] A dichloromethane solution of methanesulfonyl chloride (12.6 ml)was added dropwise to a solution of4-(2-hydroxyethyl)-5-(hydroxymethyl)thiazole (8.64 g) and triethylamine(45.4 ml) dissolved in dichloromethane (500 ml) over 20 minutes at −78°C. After stirring the reaction mixture for 15 minutes at −78° C. and 1hour at 0° C., water was added to separate an organic layer. The organiclayer was dried over anhydrous sodium sulfate. The solvent was distilledoff under reduced pressure to obtain the title compound (13.4 g) as acrude pale yellow oil.

[0515]¹H-NMR (CDCl₃) δ: 2.93(3H,s), 3.03(3H,s), 3.28(2H,t,J=6.3 Hz),4.61(2H,t,J=6.3 Hz), 5.44(2H,s), 8.84(1H,s).

Referential Example 1025-(1-Methylcyclopropyl)-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine

[0516]

[0517] 1-Methylcyclopropylamine hydrochloride (J. Org. Chem., 1989, Vol.54, p. 1815) (1.89 g) was added to dichloromethane (20 ml) containing4-(2-methane-sulfonyloxyethyl)-5-methanesulfonyloxymethylthiazole (4.46g) under ice cooling, and the mixture was stirred overnight at roomtemperature. 1-Methylcyclopropylamine hydrochloride (1.89 g) wasadditionally added, and the mixture was stirred for 20 hours at roomtemperature and 5 hours under refluxing. Dichloromethane and water wereadded to the reaction mixture to separate an organic layer. The organiclayer was dried over anhydrous sodium sulfate. The solvent was distilledoff under reduced pressure, and the residue was purified by columnchromatography on silica gel (methanol:dichloromethane=1:49) to obtainthe title compound (944 mg) as a pale yellow oil.

[0518]¹H-NMR (CDCl₃) δ: 0.40-0.50(2H,m), 0.68-0.73(2H,m), 1.16(3H,s),2.88-2.94(2H,m), 3.03(2H,t,J=5.7 Hz), 3.89(2H,br.s), 8.60(1H,s). MS(ESI) m/z: 195(M+H)⁺.

Referential Example 103 Lithium5-(1-methylcyclopropyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carboxylate

[0519]

[0520] The title compound was obtained from5-(1-methyl-cyclopropyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine in asimilar manner to Referential Example 5.

[0521]¹H-NMR (DMSO-d₆) δ: 0.39(2H,br.s), 0.56(2H,br.s), 1.10(3H,br.s),2.66(2H,br.s), 2.89(2H,br.s), 3.75(2H,br.s).

Referential Example 1045-tert-Butyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

[0522]

[0523] The title compound was obtained from4-(2-methanesulfonyloxyethyl)-5-(methanesulfonyloxy-methyl)thiazole andtert-butylamine in a similar manner to Referential Example 102.

[0524]¹H-NMR (CDCl₃) δ: 1.20(9H,s), 2.87-2.96(4H,m), 3.87(2H,s),8.59(1H,s). MS (ESI) m/z: 197(M+H)⁺.

Referential Example 105 Lithium5-tert-butyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxylate

[0525]

[0526] The title compound was obtained from5-tert-butyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine in a similarmanner to Referential Example 5.

[0527]¹H-NMR (DMSO-d₆) δ: 1.09(9H,br.s), 2.65(2H,br.s), 2.75-2.85(2H,m),3.71(2H,br.s).

Referential Example 1065-(1,1-Dimethyl-2-hydroxyethyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine

[0528]

[0529] The title compound was obtained from4-(2-methanesulfonyloxyethyl)-5-(methanesulfonyloxy-methyl)thiazole and2-amino-2-methyl-1-propanol in a similar manner to Referential Example102.

[0530]¹H-NMR (CDCl₃) δ: 1.15(6H,s), 2.91(4H,s), 3.45(2H,s), 3.87(2H,s),8.63(1H,s).

Referential Example 1075-[2-(tert-Butyldiphenylsilyloxy)-1,1-dimethylethyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

[0531]

[0532] tert-Butylchlorodiphenylsilane (1.93 g) and imidazole (994 mg)were added to a solution of5-(1,1-dimethyl-2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine(1.24 g) in N,N-dimethylformamide (5 ml) at room temperature, and themixture was stirred overnight. Water and diethyl ether were added to thereaction mixture to separate an organic layer. The organic layer wasdried over anhydrous magnesium sulfate. The solvent was distilled offunder reduced pressure, and the residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=1:2) to obtain thetitle compound (2.46 g) as a colorless oil.

[0533]¹H-NMR (CDCl₃) δ: 1.07(9H,s), 1.15(6H,s), 2.83-2.90(2H,m),2.93-3.00(2H,m), 3.63(2H,s), 3.97(2H,s), 7.35-7.48(6H,m),7.63-7.70(4H,m), 8.58(1H,s). MS (ESI) m/z: 451(M+H)⁺.

Referential Example 108 Lithium5-[2-(tert-butyldiphenylsilyloxy)-1,1-dimethyl-ethyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate

[0534]

[0535] The title compound was obtained from5-[2-(tert-butyldiphenylsilyloxy)-1,1-dimethylethyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinein a similar manner to Referential Example 5.

[0536]¹H-NMR (DMSO-d₆) δ: 1.01(9H,s), 1.11(6H,s), 2.55-2.65(2H,m),2.80-2.90(2H,m), 3.57(2H,s), 3.80(2H,br.s), 7.40-7.52(6H,m),7.60-7.65(4H,m).

Referential Example 1094,5,6,7-Tetrahydro-5,6-trimethylenethiazolo[4,5-d]-pyridazine

[0537]

[0538] 1) 4,5-Dimethylthiazole (5.00 g), N-bromo-succinimide (15.7 g)and α,α′-azobisisobutyronitrile (362 mg) were dissolved in ethylenedichloride (500 ml) at room temperature, and the solution was heatedunder reflux for 1 hour. The solvent was distilled off, and the residuewas purified by column chromatography on silica gel (hexane:diethylether=1:4) to obtain 4,5-bis(bromomethyl)thiazole (5.24 g) as a paleyellow oil.

[0539]¹H-NMR (CDCl₃) δ: 4.64(2H,s), 4.74(2H,s), 8.75(1H,s).

[0540] 2) 4,5-Bis(bromomethyl)thiazole (1.37 g) and1,2-trimethylenehydrazine hydrochloride (WO9532965) (732 mg) weresuspended in ethanol (15 ml) under ice cooling, and triethylamine (2.82ml) was added dropwise over 5 minutes. After stirring the mixture atroom temperature for 2 hours, the solvent was distilled off, anddichloromethane and a saturated aqueous solution of sodiumhydrogencarbonate were added to the residue to separate an organiclayer. The organic layer was dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure, and the residue waspurified by column chromatography on silica gel(methanol:dichloromethane=3:47) to obtain the title compound (358 mg) asyellow powder.

[0541]¹H-NMR (CDCl₃) δ: 2.10-2.25(2H,m), 3.01(4H,br.s), 3.95(2H,s),3.99(2H,br.s), 8.64(1H,s). MS (FAB) m/z: 182(M+H)⁺.

Referential Example 1104,5,6,7-Tetrahydro-5,6-tetramethylenethiazolo[4,5-d]-pyridazine

[0542]

[0543] The title compound was obtained from 4,5-bis(bromomethyl)thiazole(2.20 g) and 1,2-tetramethylenehydrazine hydrochloride (U.S. Pat. No.5,726,126) in a similar manner to Referential Example 109.

[0544]¹H-NMR (CDCl₃) δ: 1.77(4H,br.s), 2.20-3.50(4H,br), 3.92(4H,br.s),8.65(1H,s). MS (FAB) m/z: 196(M+H)⁺.

Referential Example 111 Lithium4,5,6,7-tetrahydro-5,6-trimethylenethiazolo-[4,5-d]pyridazine-2-carboxylate

[0545]

[0546] The title compound was obtained from4,5,6,7-tetrahydro-5,6-trimethylenethiazolo[4,5-d]pyridazine in asimilar manner to Referential Example 5.

[0547]¹H-NMR (DMSO-d₆) δ: 1.90-2.10(2H,m), 2.60-3.10(4H,br.s),3.65-4.00(4H,m).

Referential Example 112 Lithium4,5,6,7-tetrahydro-5,6-tetramethylenethiazolo-[4,5-d]pyridazine-2-carboxylate

[0548]

[0549] The title compound was obtained from4,5,6,7-tetrahydro-5,6-tetramethylenethiazolo[4,5-d]pyridazine in asimilar manner to Referential Example 5.

Referential Example 1136-(tert-Butoxycarbonyl)-5,7-dihydro-2-methylthiopyrrolo-[3,4-d]pyrimidine

[0550]

[0551] 1-tert-Butoxycarbonyl-3-pyrrolidone (4.57 g) was added toN,N-dimethylformamide dimethyl acetal (30 ml) at room temperature, andthe mixture was heated for 1 hour at 140° C. After allowing the reactionmixture to cool to room temperature, it was concentrated under reducedpressure. Hexane was added to the residue, and yellow powder depositedwas collected by filtration. This powder was dissolved in ethanol (100ml), and methylisothiourea sulfate (9.24 g) and sodium ethoxide (4.52 g)were added to the resultant solution at room temperature, and themixture was heated under reflux for 24 hours. Saturated saline was addedto the reaction mixture to separate an organic layer. The organic layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure, and the residue was purified by column chromatography onsilica gel (methanol:dichloromethane=1:99) to obtain the title compound(1.10 g) as pale yellow powder.

[0552]¹H-NMR (CDCl₃) δ: 1.51(9H,s), 2.57(3H,m), 4.15-4.45(4H,m),8.39(1/2H,s), 8.43(1/2H,s). MS (FAB) m/z: 268(M+H)⁺.

Referential Example 1146-(tert-Butoxycarbonyl)-5,7-dihydro-2-methylsulfonyl-pyrrolo[3,4-d]pyrimidine

[0553]

[0554] m-Chloroperbenzoic acid (1.99 g) was added to a dichloromethanesolution (20 ml) of6-(tert-butoxy-carbonyl)-5,7-dihydro-2-methylthiopyrrolo[3,4-d]-pyrimidine(1.08 g) under ice cooling, and the mixture was stirred for 5 hours. Asaturated aqueous solution of sodium sulfite, a saturated aqueoussolution of sodium hydrogen carbonate and dichloromethane were added toseparate an organic layer. The organic layer was then dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, hexane was added to the residue, and powder deposited wascollected by filtration to obtain the title compound (1.09 g) ascolorless powder.

[0555]¹H-NMR (CDCl₃) δ: 1.53(9H,s), 3.36(3H,m), 4.77-4.90(4H,m),8.77(1/2H,s), 8.81(1/2H,s). MS (FAB) m/z: 300(M+H)⁺.

Referential Example 1156-(tert-Butoxycarbonyl)-2-cyano-5,7-dihydropyrrolo-[3,4-d]pyrimidine

[0556]

[0557] Tetrabutylammonium cyanide (1.04 g) was added to a solution of6-(tert-butoxycarbonyl)-5,7-dihydro-2-methylsulfonylpyrrolo[3,4-d]pyrimidine(1.05 g) in dichloromethane (30 ml) at room temperature, and the mixturewas stirred at room temperature for 1 hour. 1N sodium hydroxide wasadded to the reaction mixture to separate an organic layer, and theorganic layer was dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (dichloromethane:acetone=20:1) toobtain the title compound (776 mg) as colorless powder.

[0558]¹H-NMR (CDCl₃) δ: 1.52(9H,s), 4.70-4.85(4H,m), 8.68-8.77(1H,m). MS(FAB) m/z: 247(M+H)⁺.

Referential Example 1166-(tert-Butoxycarbonyl)-5,7-dihydro-2-methoxycarbonyl-pyrrolo[3,4-d]pyrimidine

[0559]

[0560] Concentrated hydrochloric acid (5 ml) was added to a solution of6-(tert-butoxycarbonyl)-2-cyano-5,7-dihydropyrrolo[3,4-d]pyrimidine (776mg) in methanol (10 ml) at room temperature, and the mixture was stirredat 100° C. for 1 hour. After allowing to cool, the reaction mixture wasconcentrated under reduced pressure, and the residue was dissolve inmethanol (10 ml). Triethylamine (2.20 ml) and di-tert-butyl dicarbonate(1.37 g) were added to the solution at room temperature and stirred for1 hour. The reaction mixture was concentrated under reduced pressure,and dichloromethane and saturated saline were added to the residue toseparate an organic layer, and the organic layer was dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, and the residue was purified by column chromatography onsilica gel (methanol:dichloromethane=3:97) to obtain the title compound(317 mg) as colorless powder.

[0561]¹H-NMR (CDCl₃) δ: 1.53(9H,s), 4.09(3H,s), 4.75-4.85(4H,m),8.81(1/2H,s), 8.85(1/2H,s). MS (FAB) m/z: 280(M+H)⁺.

Referential Example 117 Lithium 1-isopropylpiperidine-4-carboxylate

[0562]

[0563] Ethyl 1-isopropylpiperidine-4-carboxylate (Farmaco., 1993, Vol.48, p. 1439) (3.43 g) was dissolved in tetrahydrofuran (60 ml), andwater (15 ml) and lithium hydroxide (421 mg) were added at roomtemperature to stir the mixture overnight. The reaction mixture wasconcentrated under reduced pressure to obtain the title compound (3.05g) as a white solid.

[0564]¹H-NMR (CD₃OD) δ: 1.05(6H,d,J=6.6 Hz), 1.65-1.78(2H,m),1.83-1.94(2H,m), 2.07(1H,tt,J=11.4,3.9 Hz), 2.20(2H,dt,J=2.7,11.6 Hz),2.60-2.72(1H,m), 2.84-2.95(2H,m).

Referential Example 118 p-Nitrophenyl 5-chloroindole-2-carboxylate

[0565]

[0566] After 5-chloroindole-2-carboxylic acid (20 g) was suspended indichloromethane (1500 ml), and N,N-dimethylformamide (2 ml) was added,thionyl chloride (11 ml) was added dropwise at room temperature. Thereaction mixture was heated overnight under reflux and then concentratedunder reduced pressure. The residue was dissolved in dichloromethane(1000 ml), and triethylamine (84.7 ml) was added to stir the mixture atroom temperature for 1 hour. The reaction mixture was concentrated underreduced pressure, and ethyl acetate and 0.2N hydrochloric acid wereadded to the residue to separate an organic layer. The organic layer wassuccessively washed with a saturated aqueous solution of sodiumhydrogencarbonate and saturated saline and then dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure toobtain the title compound (29.9 g) as a pale brown solid.

[0567]¹H-NMR (CDCl₃) δ: 7.35(1H,dd,J=9.0,1.7 Hz), 7.39-7.42(2H,m),7.45(2H,dd,J=7.3,1.7 Hz), 7.73(1H,d,J=1.0 Hz), 8.35(2H,dd,J=7.3,1.7 Hz),9.09(1H,br.s). MS (FD) m/z: 316(M⁺).

Referential Example 119 6-Chloro-4-hydroxynaphthalene-2-carboxylic acid

[0568]

[0569] 6-Chloro-4-hydroxy-2-methoxycarbonylnaphthalene (J. Chem.Research (S), 1995, p. 638) (473 mg) was dissolved in ethanol (10 ml),and a 1N aqueous solution (4.0 ml) of sodium hydroxide was added to stirthe mixture for 24 hours at room temperature. Thereafter, the reactionmixture was stirred for 1 hour at 60° C. and 6 hours at 70° C., and thesolvent was distilled off under reduced pressure. An 1N aqueous solutionof hydrochloric acid and ethyl acetate were added to separate an organiclayer. The organic layer was dried over anhydrous magnesium sulfate, andthe solvent was distilled off under reduced pressure to obtain the titlecompound (442 mg) as a pale yellow solid.

[0570]¹H-NMR (DMSO-d₆) δ: 7.43(1H,d,J=1.2 Hz), 7.58(1H,dd,J=8.8,2.2 Hz),8.07-8.09(2H,m), 8.13(1H,d,J=2.2 Hz), 10.69(1H,s), 12.99(1H,br.s). MS(ESI) m/z: 223(M+H)⁺.

Referential Example 120 Isolation of Optically Active Substances of(±)-trans-N-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediamine

[0571]

[0572](±)-trans-N-[(5-Methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediamine(1.83 g) was dissolved in 2-propanol (15 ml), and the solution waspurified by HPLC. As a column, CHIRALPAK AD was used to conduct elutionat a flow rate of 6 ml/min using a solvent ofhexane:2-propanol:diethylamine=75:25:0.5. Fractions eluted after 32minutes and 45 minutes were separately collected to obtain (1S,2S)-form(675 mg) as an orange oil and (1R,2R)-form (673 mg) as a brown oil.

Referential Example 121 1,2-Epoxy-4-methoxycarbonylcyclopentane

[0573]

[0574] 3-Cyclopentenecarboxylic acid (J. Org. Chem., 1984, Vol. 49, p.928) (2.42 g) was dissolved in methanol (8 ml) and 2,2-dimethoxypropane(32 ml), and trimethylsilyl chloride (253 μl) was added dropwise to stirthe mixture at room temperature for 6.5 hours. The solvent was distilledoff under reduced pressure, and the residue was dissolved indichloromethane (50 ml), to which m-chloroperbenzoic acid (70%, 4.93 g)was added under ice cooling. After the mixture was heated to roomtemperature and stirred for 5 hours, a saturated aqueous solution ofsodium hydrogencarbonate was added to separate an organic layer. Theorganic layer was washed with a saturated aqueous solution of sodiumhydrogencarbonate and then dried over anhydrous sodium sulfate. Theorganic layer was concentrated under reduced pressure, and the residuewas purified by column chromatography on silica gel (hexane:ethylacetate=2:1) to obtain the title compound (1.59 g) as a colorless oil.

[0575]¹H-NMR (CDCl₃) δ: 1.86-1.92(2H,m), 2.32-2.38(2H,m),2.61-2.70(1H,m), 3.53(2H,s), 3.68(3H,s).

Referential Example 122(1R*,2R*)-1,2-Dihydroxy-4-methoxycarbonylcyclopentane

[0576]

[0577] 1,2-Epoxy-4-methoxycarbonylcyclopentane (37.7 g) was dissolved ina mixed solvent of tetrahydrofuran (500 ml) and water (500 ml), andsulfuric acid (13.3 ml) was added dropwise under ice cooling to stir themixture at room temperature for 4 hours. Sodium carbonate and sodiumhydrogencarbonate were added to the reaction mixture to make the mixtureneutral or weakly alkaline, and the solvent was distilled off underreduced pressure. The residue was extracted with dichloromethane andethyl acetate, insoluble matter was removed by filtration, and thefiltrate was concentrated under reduced pressure to obtain the titlecompound (35.5 g) as a pale yellow oil.

[0578]¹H-NMR (CDCl₃) δ: 1.81-1.93(2H,m), 2.20-2.37(2H,m), 2.84(1H,br.s),2.99-3.07(1H,m), 3.70(3H,s), 3.97-4.01(1H,s), 4.08-4.12(1H,m),4.56(1H,br.s).

Referential Example 123(1R*,2R*)-1,2-7Bis(methanesulfonyloxy)-4-methoxycarbonyl-cyclopentane

[0579]

[0580] (1R*,2R*)-1,2-Dihydroxy-4-methoxycarbonyl-cyclopentane (700 mg)was dissolved in dichloromethane (10 ml), and triethylamine (3.63 ml)was added. After purging with argon, the mixture was cooled to −78° C.and methanesulfonyl chloride (1.01 ml) was added dropwise. After themixture was heated to 0° C. and stirred for 2 hours, water was added toconduct liquid separation. An organic layer was separated and dried overanhydrous sodium sulfate, and the solvent is distilled off under reducedpressure. The residue was purified by flash column chromatography onsilica gel (ethyl acetate:hexane=1:1) to obtain the title compound (521mg) as a pale yellow oil.

[0581]¹H-NMR (CDCl₃) δ: 2.21-2.29(2H,m), 2.42-2.63(2H,m),3.02-3.14(7H,m), 3.72(3H,s), 5.07-4.11(1H,m), 5.13-5.17 (1H,m). MS (FAB)m/z: 317(M+H)⁺.

Referential Example 124 (1R*,2R*)-1,2-Diazido-4-methoxycarbonylcyclopentane

[0582]

[0583] (1R* ,2R*)-1,2-Bis(methanesulfonyloxy)-4-methoxy-carbonylcyclopentane (27.3 g) wasdissolved in N,N-dimethylformamide (200 ml), and sodium azide (33.7 g)was added to stir the mixture at 75° C. for 16 hours. After allowing thereaction mixture to cool, water was added, and the reaction mixture wasextracted with ether. The resultant organic layer was washed with asaturated aqueous solution of sodium hydrogen carbonate and saturatedsaline and then dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (hexane:ethyl acetate=2:1) to obtainthe title compound (11.53 g) as a pale yellow oil.

[0584]¹H-NMR (CDCl₃) δ: 1.92-2.02(2H,m), 2.34-2.43(2H,m),2.96-3.04(1H,m), 3.72(3H,s), 3.75-3.80(1H,m), 3.85-3.90(1H,m).

Referential Example 125 (1R*,2R*)-N¹-[(5-Chloroindol-2-yl)carbonyl]-4-methoxycarbonyl-1,2-cyclopentanediamine (Mixture ofStereoisomers)

[0585]

[0586] trans-1,2-Diazido-4-methoxycarbonylcyclopentane (10.6 g) wasdissolved in tetrahydrofuran (200 ml), and 10% palladium on carbon (3 g)was added to stir the mixture at room temperature for 13 hours in ahydrogen atmosphere. The catalyst was removed by filtration, and thesolvent was distilled off under reduced pressure. A solution ofp-nitrophenyl 5-chloroindole-2-carboxylate (13.6 g) inN,N-dimethylformamide (100 ml) was added dropwise to the residue underice cooling. The mixture was stirred for 2 hours at 0° C. and then 11hours at room temperature. A saturated aqueous solution of sodiumhydrogencarbonate was added to the reaction mixture to conductextraction with dichloromethane. The resultant organic layer was washedwith a saturated aqueous solution of sodium hydrogencarbonate and thendried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by column chromatographyon silica gel (dichloromethane:methanol=19:1→9:1) to obtain the titlecompound (4.22 g) as a pale yellow solid.

[0587]¹H-NMR (DMSO-d₆) δ: 1.51-1.81(2H.m), 2.05-2.34(2H,m),2.93-3.04(1H,m), 3.15-3.22(1H,m), 3.62,3.63(3H,each s), 3.87-3.94(1H,m),7.15-7.19(2H.m), 7.43(1H,d,J=8.8 Hz), 7.70(1H,d,J=2.0 Hz),8.37-8.42(1H,m), 11.74(1H,br.s). MS (FAB) m/z: 336(M+H)⁺.

Referential Example 126 (1R*,2R*)-1,2-Dihydroxy-4-methoxycyclopentane

[0588]

[0589] 60% Sodium hydride (800 mg) was added portionwise to a solutionwith 3-cyclopentene-1-ol (1.68 g) and methyl iodide (1.25 ml) dissolvedin tetrahydrofuran (20 ml) under ice cooling, and the mixture wasstirred overnight at room temperature. Water and diethyl ether was addedto the reaction mixture to separate an organic layer, the organic layerwas dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure cooling with ice to obtain crude4-methoxy-1-cyclopentene.

[0590] 88% Formic acid (90 ml) and 30% hydrogen peroxide (3.17 ml) wereadded to 4-methoxy-1-cyclopentene thus obtained, and the mixture wasstirred overnight at room temperature. The reaction mixture wasconcentrated under reduced pressure, and a 35% aqueous solution ofsodium hydroxide was added to the residue to alkalify the reactionmixture, followed by stirring at 50° C. for 10 minutes. The reactionmixture was cooled to room temperature and extracted with ethyl acetateto dry the organic layer over anhydrous magnesium sulfate. The solventwas distilled off, and the residue was purified by column chromatographyon silica gel (methanol:dichloromethane=5:95) to obtain the titlecompound (1.21 g) as a colorless oil.

[0591]¹H-NMR (CDCl₃) δ: 1.65-1.85(2H,m), 2.15-2.30(2H,m), 3.28(3H,s),3.90-4.00(2H,m), 4.26(1H,br.s).

Referential Example 127 (1R*,2R*)-1,2-Diazido-4-methoxycyclopentane

[0592]

[0593] (1R*,2R*)-1,2-Dihydroxy-4-methoxycyclopentane (1.21 g) andtriethylamine (7.66 ml) were dissolved in dichloromethane (20 ml), andmethanesulfonyl chloride (2.13 ml) was added dropwise over 20 minutes at−78° C. After completion of drop addition, the mixture was warmed to 0°C. and stirred for 80 minutes to obtain crude (1R*,2R*)-1,2-bis(methanesulfonyloxy)-4-methoxy-cyclopentane. This product was dissolvedin N,N-dimethylformamide (20 ml), and sodium azide (3.57 g) was added.The mixture was stirred at 65° C. for 22 hours. Sodium azide (3.57 g)was additionally added to stir the mixture at 70° C. for 2 days. Thereaction mixture was allowed to cool, and water and diethyl ether wasadded to separate an organic layer. The organic layer was dried overanhydrous magnesium sulfate. The solvent was distilled off, and theresidue was purified by column chromatography on silica gel(hexane:ethyl acetate=2:1) to obtain the title compound (584 mg) as acolorless liquid.

[0594]¹H-NMR (CDCl₃) δ: 1.65-1.80(2H,m), 2.05-2.18(1H,m),2.25-2.40(1H,m), 3.21(3H,s), 3.55-3.65(1H,m), 3.75-3.90(2H,m).

Referential Example 128 (1R*,2R*)-4-Methoxycyclopentane-1,2-diaminehydrochloride

[0595]

[0596] (1R*,2R*)-1,2-Diazido-4-methoxycyclopentane (584 mg) wasdissolved in ethanol, and 10% palladium on carbon (321 mg) was added toconduct hydrogenation at normal temperature and normal pressure for 2days. After removing the catalyst by filtration, the reaction mixturewas concentrated, and a 1N ethanol solution of hydrochloric acid andethyl acetate were added to the residue. The mixture was concentrated toobtain the title compound (488 mg).

[0597]¹H-NMR (CDCl₃) δ: 1.72-1.83(1H,m), 1.91-2.03(1H,m),2.07-2.18(1H,m), 2.37-2.50(1H,m), 3.19(3H,s), 3.55-3.75(2H,br),3.85-3.95(1H,m), 8.60-8.90(6H,br). MS (ESI) m/z: 261(2M+H)⁺.

Referential Example 129 trans-4-Benzyloxy-1,2-dihydroxycyclopentane

[0598]

[0599] The title compound was obtained by benzylating3-cyclopentene-1-ol with benzyl bromide and then treating the productwith formic acid-hydrogen peroxide in a similar manner to ReferentialExample 126.

[0600]¹H-NMR (CDCl₃) δ: 1.62(1H,br.s), 1.75-1.95(2H,m),2.21(1H,d.t,J=14.2 and 5.9 Hz), 2.33(1H,d.d,J=14.7 and 6.9 Hz),2.57(1H,br.s), 3.96(1H,s), 4.15(1H,s), 4.30(1H,s), 4.48(2H,s),7.20-7.40(5H,m).

Referential Example 130 trans-4-Benzyloxy-1,2-diazidocyclopentane

[0601]

[0602] The title compound was obtained fromtrans-4-benzyloxy-1,2-dihydroxycyclopentane in a similar manner toReferential Example 127.

[0603]¹H-NMR (CDCl₃) δ: 1.75-1.90(2H,m), 2.15-2.30(1H,m),2.35-2.50(1H,m), 3.67(1H,d.d,J=14.9 and 6.8 Hz), 3.96(1H,d.d,J=15.2 and6.8 Hz), 4.00-4.10(1H,m), 4.44(1H,d.d,J=11.8 Hz), 4.48(1H,d.d,J=11.8Hz), 7.20-7.40(5H,m).

Referential Example 131 trans-4-Benzyloxy-1,2-cyclopentanediamine

[0604]

[0605] Lithium aluminum hydride (2.0 g) was suspended in tetrahydrofuran(50 ml), and a tetrahydrofuran solution (30 ml) oftrans-1,2-diazido-4-benzyloxycyclopentane (6.74 g) was added dropwiseover 70 minutes under an argon atmosphere. After 1 hour, the reactionmixture was cooled with ice, and water (2 ml), a 15% aqueous solution (2ml) of sodium hydroxide and water (3 ml) were slowly added dropwise.After the mixture was stirred at room temperature for 2 hours, insolublematter was removed by filtration, and the filtrate was concentrated toobtain the title compound (5.37 g) as a crude pale yellow oil.

[0606]¹H-NMR (CDCl₃) δ: 120-1.80(6H,m), 2.18(1H,d.d,J=13.9 and 7.1 Hz),2.41(1H,d.t,J=13.5 and 7.1 Hz), 2.71(1H,q,J=7.6 Hz), 3.04(1H,q,J=7.6Hz), 3.95-4.05(1H,m), 4.45(2H,s), 7.20-7.40(5H,m). MS (ESI) m/z:207(M+H)⁺.

Referential Example 132 Mixture of(1R*,2R*,4R*)-4-benzyloxy-N¹-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclopentanediamineand (1R*,2R*,4S*)-4-benzyloxy-N¹-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclopentanediamine

[0607]

[0608] The title compound was obtained from(±)-trans-4-benzyloxy-1,2-cyclopentanediamine and5-chloroindole-2-carboxylic acid in a similar manner to ReferentialExample 30.

[0609]¹H-NMR (CDCl₃) δ: 1.60-2.20(4H,m), 3.30-3.60(3H,m),3.95-4.45(2H,m), 4.43,4.45(total 2H,each s), 7.10-7.50(8H,m),7.68,7.70(total 1H,each s), 8.67,8.69(total 1H,d,J=8.3 Hz),11.87(1H,br.s). MS (ESI) m/z: 384(M+H)⁺.

Referential Example 133 (1R*,2R*)-4-Benzyloxymethyl-1,2-cyclopentanediol

[0610]

[0611] The title compound was obtained by benzylating(1R*,2R*)-4-hydroxymethyl-1-cyclopentene. (J. Heterocycl. Chem., 1989,Vol. 26, p. 451) with benzyl bromide and then reacting the product withformic acid-hydrogen peroxide in a similar manner to Referential Example126.

[0612]¹H-NMR (CDCl₃) δ: 1.44-1.52(1H,m), 1.77-1.85(1H,m),1.89-1.97(1H,m), 2.25-2.35(1H,m), 2.46-2.58(1H,m), 3.40-3.50(2H,m),3.89(1H,br.s), 4.08(1H,br.s), 4.54(2H,s), 7.27-7.39(5H,m). MS (FAB) m/z:223(M+H)⁺.

Referential Example 134(1R*,2R*)-4-Benzyloxymethyl-1,2-cyclopentanediamine

[0613]

[0614] (1R*,2R*)-4-Benzyloxymethyl-1,2-diazidocyclopentane was obtainedfrom (1R*,2R*)-4-benzyloxymethyl-1,2-cyclopentanediol in a similarmanner to Referential Example 127. The title compound was obtained in asimilar manner to Referential Example 128 without purifying thisproduct.

Referential Example 135(1R*,2R*)-4-Benzyloxymethyl-N¹-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclopentanediamine

[0615]

[0616] The title compound was obtained from(1R*,2R*)-4-benzyloxymethyl-1,2-cyclopentanediamine in a similar mannerto Referential Example 125.

[0617]¹H-NMR (DMSO-d₆) δ: 1.07-1.15(0.5H,m), 1.26-1.35(0.5H,m),1.47-1.55(0.5H,m), 1.61-1.79(1H,m), 1.83-1.92(0.5H,m),1.99-2.10(0.5H,m), 2.12-2.20(0.5H,m), 2.27-2.40(1H,m), 3.10-3.20(1H,m),3.33-3.39(2H,m), 3.81-3.92(1H,m), 4.48(2H,s), 7.13-7.20(2H,m),7.22-7.39(5H,m), 7.43(1H,d,J=8.5 Hz), 7.69(1H,d,J=2.2 Hz),8.34(1H,t,J=7.1 Hz). MS (FAB) m/z: 398(M+H)⁺.

Referential Example 136(±)-trans-4,4-Bis(methoxymethyl)-1,2-dihydroxy-cyclopentane

[0618]

[0619] The title compound was obtained from1,1-bis(hydroxymethyl)-3-cyclopentene (J. Med., Chem., 1991, Vol. 34, p.3316) in a similar manner to Referential Example 126.

[0620]¹H-NMR (CDCl₃) δ: 1.57(2H,d,J=14.7 Hz), 2.16(2H,dd,J=14.7,4.9 Hz),3.23(4H,s), 3.40(6H,s), 3.90-3.98(1H,m) MS (FAB) m/z: 191(M+H)⁺.

Referential Example 137(±)-trans-4,4-Bis(methoxymethyl)-1,2-cyclopentane-diamine

[0621]

[0622] (±)-trans-4,4-Bis(methoxymethyl)-1,2-diazido-cyclopentane wasobtained from(±)-trans-4,4-bis-(methoxymethyl)-1,2-dihydroxycyclopentane in a similarmanner to Referential Example 127. The title compound was obtained in asimilar manner to Referential Example 128 without purifying thisproduct.

[0623]¹H-NMR (CDCl₃) δ: 1.19-1.25(2H,m), 1.89(2H,dd,J=13.2,6.6 Hz),2.70-2.77(2H,m), 3.20(4H,s), 3.33(6H,s). MS (FAB) m/z: 189(M+H)⁺.

Referential Example 138(±)-trans-4,4-Bis(methoxymethyl)-N¹-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclopentanediamine

[0624]

[0625] The title compound was obtained from(±)-trans-4,4-bis(methoxymethyl)-1,2-clopentanediamine in a similarmanner to Referential Example 125.

[0626]¹H-NMR (CDCl₃) δ: 1.42(1H,dd,J=14.0,3.5 Hz), 1.58(1H,dd,J=14.0,3.5Hz), 2.05(1H,dd,J=14.0,6.9 Hz), 3.31(1H,dd,J=14.0,6.9 Hz).,3.25-3.55(11H,m), 4.16-4.23(1H,m), 6.69(1H,s), 7.19(1H,dd,J=8.8,1.7 Hz),7.36(1H,d,J=8.8 Hz), 7.58(1H,s), 7.65(1H,d,J=7.6 Hz). MS (FAB) m/z:366(M+H)⁺.

Referential Example 139(±)-trans-4,4-Bis(benzyloxymethyl)-1,2-cyclopentanediol

[0627]

[0628] The title compound was obtained by benzylating1,1-bis(hydroxymethyl)-3-cyclopentene (J. Med., Chem., 1991, Vol. 34, p.3316) with benzyl bromide and then treating the product with formicacid-hydrogen peroxide in a similar manner to Referential Example 126.

[0629]¹H-NMR (CDCl₃) δ: 1.58-1.65(2H,m), 2.21(2H,dd,J=14.5,4.9 Hz),3.27-3.34(4H,m), 3.93(2H,dd,J=7.5,4.9 Hz), 4.55(4H,s), 7.27-7.39(10H,m).MS (FAB) m/z: 343(M+H)⁺.

Referential Example 140(±)-trans-4,4-Bis(benzyloxymethyl)-1,2-cyclopentane-diamine

[0630]

[0631] (±)-trans-4,4-Bis(benzyloxymethyl)-1,2-diazidocyclopentane wasobtained from (±)-trans-4,4-bis(benzyloxymethyl)-1,2-cyclopentanediol ina similar manner to Referential Example 127. The title compound wasobtained in a similar manner to Referential Example 128.

[0632]¹H-NMR (CDCl₃) δ: 1.20-1.28(2H,m), 1.96(2H,dd,J=13.2,6.6 Hz),2.69-2.78(2H,m), 3.32(4H,s), 4.50(4H,s), 7.27-7.38(10H,m). MS (FAB) m/z:341(M+H)⁺.

Referential Example 141 (±)-trans-4,4-Bis(benzyloxymethyl)-N¹-(5-Chloroindol-2-yl)carbonyl]-1,2-cyclopentanediamine

[0633]

[0634] The title compound was obtained from(±)-trans-4,4-bis(benzyloxymethyl)-1,2-cyclopentanediamine and5-chloroindole-2-carboxylic acid in a similar manner to ReferentialExample 30.

[0635]¹H-NMR (DMSO-d₆) δ: 1.33-1.41(1H,m), 1.45-1.54(1H,m),1.86-2.00(2H,m), 3.15-3.23(1H,m), 3.26-3.38(4H,m), 3.98-4.07(1H,m),4.51(2H,d,J=4.2 Hz), 7.14(1H,s), 7.17(1H,dd.J=8.8,2.0 Hz),7.25-7.39(11H,m), 7.43(1H,d,J=8.5 Hz), 7.70(1H,d,J=2.0 Hz), 8.41(1H,d,J=7.5 Hz) MS (FAB) m/z: 518(M+H)⁺.

Referential Example 142 Lithium5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[4,5-d]-pyridazine-2-carboxylate

[0636]

[0637] 1) After 4,5-bis(bromomethyl)thiazole (600 mg) synthesized in 1)of Referential Example 109 was dissolved in ethanol (20 ml), and1,2-dimethylhydrazine hydrochloride (294 mg) was added under icecooling, triethylamine (1.23 ml) was added at a time, and the mixturewas stirred for 30 minutes at room temperature and 30 minutes at 50° C.The solvent was distilled off, and the residue was purified by columnchromatography on silica gel (methanol:dichloromethane=1:19) to obtain5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[4,5-d]-pyridazine (90 mg) as acolorless oil.

[0638]¹H-NMR (CDCl₃) δ: 2.43(3H,s), 2.56(3H,s), 3.92(2H,s),4.06(2H,br.s), 8.68(1H,s). MS (FAB) m/z: 170(M+H)⁺.

[0639] 2) The title compound was obtained from5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[4,5-d]pyridazine in a similarmanner to Referential Example 5.

[0640]¹H-NMR (DMSO-d₆) δ: 2.28(3H,s), 2.39(3H,s), 3.66(2H,br.s),3.88(2H,br.s).

Referential Example 143 Lithium5-tert-butyl-4,6-dihydro-5H-pyrrolo[3,4-d]-thiazole-2-carboxylate

[0641]

[0642] 1) 4,5-bis(bromomethyl)thiazole (1.50 g) synthesized in 1) ofReferential Example 109 was dissolved in dioxane (30 ml), and a dioxanesolution (10 ml) of tert-butylamine (2.03 ml) was added dropwise to thesolution over 1 hour at room temperature. After stirring at roomtemperature for 5 hours, the reaction mixture was concentrated, anddichloromethane and a saturated aqueous solution of sodiumhydrogencarbonate were added to the residue to separate an organiclayer. The organic layer was dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure, and the residue waspurified by column chromatography on silica gel(methanol:dichloromethane=1:19) to obtain5-tert-butyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole (407 mg) as a paleyellow oil.

[0643]¹H-NMR (CDCl₃) δ: 1.19(9H,s), 4.05-4.07(2H,m),4.10-4.14(2H,br.s.), 8.68(1H,s). MS (ESI) m/z: 183(M+H)⁺.

[0644] 2) The product (407 mg) formed above was dissolved in diethylether (3 ml), and n-butyllithium (1.53N hexane solution, 1.60 ml) wasadded dropwise at −78° C. in an argon atmosphere to stir the mixture for30 minutes under ice cooling. The reaction mixture was cooled again to−78° C. After blowing carbon dioxide into the reaction mixture for 20minutes, it was heated to room temperature. The reaction mixture wasconcentrated under reduced pressure to obtain the title compound (580mg) as crude brown powder.

Referential Example 1441-(tert-Butoxycarbonyl)-4-(methoxycarbonylethynyl)-piperidine

[0645]

[0646] n-Butyllithium (1.57N hexane solution, 3.11 ml) was addeddropwise to a solution with1-(tert-butoxycarbonyl)-4-(2,2-dibromovinyl)piperidine (WO9806720) (900mg) dissolved in tetrahydrofuran (16 ml) at −78° C., and the mixture wasstirred for 1 hour. Methyl chlorocarbonate (377 μl) was added to thereaction mixture to heat the mixture to room temperature in 1 hour.Diethyl ether (30 ml) and a saturated aqueous A solution (50 ml) ofammonium chloride were added to the reaction mixture to separate anorganic layer. The organic layer was dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, and theresidue was purified by column chromatography on silica gel(hexane:ethyl acetate=4:1) to obtain the title compound (634 mg) as acolorless transparent oil.

[0647]¹H-NMR (CDCl₃) δ: 1.45(9H,s), 1.58-1.70(2H,m), 1.78-1.88(2H,m),2.68-2.76(1H,m), 3.14-3.23(2H,m), 3.67-3.77(2H,m), 3.77(3H,s). MS (ESI)m/z: 268(M+H)⁺.

Referential Example 1451-(tert-Butoxycarbonyl)-4-hydroxy-4-(methoxycarbonyl-ethynyl)piperidine

[0648]

[0649] n-Butyllithium (1.57N hexane solution, 6.4 ml) was added dropwiseto a solution of methyl propionate (893 μl) in tetrahydrofuran (50 ml)at −78° C. After stirring for 30 minutes, a solution of1-(tert-butoxycarbonyl)-4-piperidone (2.0 g) in tetrahydrofuran (10 ml)was added, and the mixture was gradually warmed to room temperature andstirred overnight. A saturated aqueous solution (50 ml) of ammoniumchloride and ethyl acetate (50 ml) were added to the reaction mixture toseparate an organic layer. The organic layer was dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure,and the residue was purified by column chromatography on silica gel(hexane:ethyl acetate=3:1) to obtain the title compound (1.78 g) as apale yellow caramel-like substance.

[0650]¹H-NMR (CDCl₃) δ: 1.46(9H,s), 1.72-1.82 (2H,m), 1.90-2.00(2H,m),2.39(1H,br.s), 3.30-3.38(2H,m), 3.67-3.77(2H,m), 3.79(3H,s). MS (ESI)m/z: 284(M+H)⁺.

Referential Example 1461-(tert-Butoxycarbonyl)-4-(methoxycarbonylethynyl)-1,2,3,6-tetrahydropyridine

[0651]

[0652] Pyridine (1.12 ml) and trifluoromethanesulfonic anhydride (875μl) were added dropwise to a solution of1-(tert-butoxycarbonyl)-4-hydroxy-4-(methoxycarbonyl-ethynyl)piperidine(490 mg) in dichloromethane (15 ml) at −78° C. After heating the mixtureto room temperature in 1 hour, a saturated aqueous solution (50 ml) ofsodium hydrogencarbonate and dichloromethane (10 ml) were added to thereaction mixture to separate an organic layer. The organic layer wasdried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by column chromatographyon silica gel (hexane:ethyl acetate=5:1→2:1) to obtain the titlecompound (249 mg) as a pale yellow oil.

[0653]¹H-NMR (CDCl₃) δ: 1.48(9H,s), 2.26-2.33(2H,m), 3.51(2H,t,J=5.6Hz), 3.79(3H,s), 4.00-4.05(2H,m), 6.36(1H,br.s).

Referential Example 147cis-N¹,N²-Bis(tert-butoxycarbonyl)-1,2-cyclohexanediamine

[0654]

[0655] cis-1,2-Cyclohexanediamine (4.79 ml) was dissolved indichloromethane (200 ml), and di-tert-butyl carbonate (18.3 g) and a 1Naqueous solution (100 ml) of sodium hydroxide were added to stir themixture at room temperature for 2 hours. An organic layer was separated,washed with saturated saline and then dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure to obtainthe title compound (17.2 g) as a white solid.

[0656]¹H-NMR (CDCl₃) δ: 1.40-1.71(26H,m), 3.79(2H,br.s),4.84-4.86(2H,m). MS (ESI) m/z: 315(M+H)⁺.

Referential Example 148cis-N¹,N²-Bis(tert-butoxycarbonyl)-N¹,N²-dimethyl-1,2-cyclohexanediamine

[0657]

[0658] N,N-Dimethylformamide (20 ml) was cooled to 0° C., and 60% sodiumhydride (800 mg) was added.cis-N¹,N²-Bis(tert-butoxycarbonyl)-1,2-cyclohexanediamine (3.14 g) wasadded to the reaction mixture, and the mixture was stirred for 30minutes at the same temperature and then 4 hours at room temperature. Asaturated aqueous solution of sodium hydrogencarbonate was added to thereaction mixture to conduct extraction with hexane. The resultantextract was dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure to obtain the title compound (2.16g) as a pale yellow solid.

[0659]¹H-NMR (CDCl₃) δ: 1.43-1.83(26H,m), 2.89(6H,br.s), 4.35(2H,br.s).MS (ESI) m/z: 343(M+H)⁺.

Referential Example 149 cis-N¹,N²-Dimethyl-1,2-cyclohexanediaminehydrochloride

[0660]

[0661]cis-N¹,N²-Bis(tert-butoxycarbonyl)-N¹,N²-dimethyl-1,2-cyclohexanediamine(2.15 g) was dissolved in a saturated ethanol solution of hydrochloricacid, and the solution was stirred at room temperature for 30 minutes.The solvent was distilled off under reduced pressure, ethyl acetate wasadded to the residue, and solids were collected by filtration to obtainthe title compound (1.19 g) as a pale yellow solid.

[0662]¹H-NMR (DMSO-d₆) δ: 1.40-1.41(2H,m), 1.71-1.92(6H,m), 2.65(6H,s),3.61(2H,br.s) MS (ESI) m/z: 143(M+H)⁺.

Referential Example 150cis-N¹-[(1-Benzenesulfonyl-5-chloroindol-2-yl)carbonyl]-N¹,N²-dimethyl-1,2-cyclohexanediamine

[0663]

[0664] 1-Benzenesulfonyl-5-chloroindole-2-carboxylic acid (890 mg) wasdissolved in chloroform (20 ml), and thionyl chloride (2 ml) andN,N-dimethylformamide (one drop) were added to stir the mixture at 65°C. for 45 minutes. The solvent was distilled off under reduced pressure,and dichloromethane (10 ml) and pyridine (10 ml) were added to theresidue. A solution (10 ml) of cis-N¹,N²-dimethyl-1,2-cyclohexanediaminehydrochloride (855 mg) in a 1:1 mixed solution (10 ml) ofdichloromethane and pyridine was added to the reaction mixture, and themixture was stirred at room temperature for 3 days. The reaction mixturewas heated and stirred at 55° C. for additional 4 hours, and water wasadded to separate an organic layer. The organic layer was washed withwater and dried over anhydrous sodium sulfate. The solvent was distilledoff under reduced pressure, and the residue was purified by flash columnchromatography on silica gel (hexane:ethyl acetate=2:1) to obtain thetitle compound (738 mg) as an ocher solid.

[0665] MS (ESI) m/z: 460(M+H)⁺.

Referential Example 151(1R,2S)-N¹-tert-Butoxycarbonyl-1,2-cyclohexanediamine

[0666]

[0667] The title compound was synthesized from(1R,2S)-2-amino-1-cyclohexanol (J. Org. Chem., 1985, Vol. 50, p. 4154)in a similar manner to Referential Examples 44 to 47.

[0668]¹H-NMR (CDCl₃) δ: 1.00-1.70(8H,m), 1.45(9H, s), 2.95-3.05(1H,m),3.60(1H,br.s), 5.00(1H,br.s). MS (FAB) m/z: 215(M+H)⁺.

Referential Example 152(1S,2R)-N¹-[(5-Chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[0669]

[0670](1R,2S)-N¹-(tert-Butoxycarbonyl)-N²-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminewas obtained from(1R,2S)-N¹-(tert-butoxycarbonyl)-1,2-cyclohexanediamine in a similarmanner to Referential Example 52, and deprotection was then conductedwith a saturated ethanol solution of hydrochloric acid in a similarmanner to Referential Example 54 to obtain the title compound.

[0671]¹H-NMR (DMSO-d₆) δ: 1.30-1.50(2H,m), 1.55-1.95(6H,m),3.02(1H,br.s), 3.90-3.97(1H,br.s), 7.15-7.19(2H,m), 7.43(1H,d,J=8.8 Hz),7.68(1H,d,J=2.0 Hz), 7.90(1H,d,J=8.1 Hz)

Referential Example 153 (±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-4-cyclohexene-1,2-diamine

[0672]

[0673] The title compound was obtained fromcis-4-cyclohexene-1,2-diamine hydrochloride (EP 154788) and5-chloroindole-2-carboxylic acid in a similar manner to ReferentialExample 30.

[0674]¹H-NMR (DMSO-d₆) δ: 1.93(m,1H), 2.05(m,1H), 2.36(m,2H),2.91(dt,1H,J=5.6,10.3 Hz), 3.82(m,1H), 5.60(s,2H), 7.17(m,2H),7.43(d,1H,J=8.8 Hz), 7.69(d,1H,J=1.7 Hz), 8.32(d,1H,J=8.6 Hz).

Referential Example 154 Ethyl (1R*,3R*,4S*)-3,4-epoxycyclohexane-1-carboxylate

[0675]

[0676] (1R*,4R*,5R*) -4-Iodo-6-oxabicyclo [3.2.1]octan-7-one (J. Org.Chem., 1996, Vol. 61, p. 8687) (14.3 g) was dissolved in ethanol (130ml), a 2N aqueous solution (34.5 ml) of sodium hydroxide was added underice cooling, and the mixture was then stirred at room temperature for 7hours. After the solvent was distilled off under reduced pressure, andwater was added to the residue to conduct extraction withdichloromethane, the extract was dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure, and the residuewas purified by column chromatography on silica gel (hexane:ethylacetate=83:17) to obtain the title compound (6.54 g) as a colorless oil.

[0677]¹H-NMR (CDCl₃) δ: 1.25 (3H,t, J=7.1 Hz), 1.50-1.70(2H,m),1.71-1.82(1H,m), 2.08-2.28(4H,m), 3.16(2H,s), 4.12 (2H,q, J=7.1 Hz)

Referential Example 155 Ethyl(1R*,3S*,4S*)-3-azido-4-hydroxycyclohexane-1-carboxylate

[0678]

[0679] Ethyl (1R*,3R*,4S*)-3,4-epoxycyclohexane-1-carboxylate (13.6 g)was dissolved in N,N-dimethyl-formamide (100 ml), ammonium chloride(6.45 g) and sodium azide (7.8 g) were successively added at roomtemperature, and the mixture was then stirred at 75° C. for 12 hours.The solvent was concentrated to about 1/3, and the residue was dilutedwith water and ethyl acetate to conduct stirring for 3 minutes. Theresultant organic layer was washed with water and saturated saline anddried over anhydrous magnesium sulfate. The solvent was distilled offunder reduced pressure, and the residue was purified by columnchromatography on silica gel (ethyl acetate:hexane=1:4) to obtain thetitle compound (15.8 g) as a colorless oil.

[0680]¹H-NMR (CDCl₃) δ: 1.28(3H,t,J=7.1 Hz), 1.37-1.67(2H,m),1.86-1.95(1H,m), 2.04-2.18(2H,m), 2.32-2.43(1H,m), 2.68-2.78(1H,m),3.40-3.60(2H,m), 4.17(2H,q,J=7.1 Hz).

Referential Example 156 Ethyl(1R*,3S*,4S*)-3-(tert-butoxycarbonylamino)-4-hydroxycyclohexane-1-carboxylate

[0681]

[0682] Ethyl (1R*,3S*,4S*)-3-azido-4-hydroxycyclohexane-1-carboxylate(100 mg) and di-tert-butyl dicarbonate (133 mg) were dissolved in ethylacetate (12 ml) and a catalytic amount of 10% palladium on carbon wasadded to stir the mixture at room temperature for 12 hours in a hydrogenatmosphere. After insoluble matter was removed by filtration, thesolvent was distilled off under reduced pressure, and the residue waspurified by column chromatography on silica gel (hexane:ethylacetate=3:1) to obtain the title compound (145 mg) as a colorless solid.

[0683]¹H-NMR (CDCl₃) δ: 1.28 (3H,t, J=7.1 Hz), 1.45(9H,s),1.38-1.57(2H,m), 1.86-1.95(1H,m), 2.05-2.17(1H,m), 2.29-2.39(2H,m),2.61-2.68(1H,m), 3.25-3.66(3H,m), 4.17(2H,q,J=7.1 Hz), 4.53(1H,br.s).

Referential Example 157 Ethyl(1R*,3S*,4R*)-4-azido-3-(tert-butoxycarbonylamino)-cyclohexane-1-carboxylateand ethyl(1R*,3S*,4S*)-4-azido-3-(tert-butoxycarbonylamino)cyclohexane-1-carboxylate

[0684]

[0685] After ethyl(1R*,3S*,4S*)-3-tert-butoxycarbonylamino-4-hydroxycyclohexane-1-carboxylate(16 g) and triethylamine (38 ml) were dissolved in dichloromethane (150ml), and the solution was cooled to −78° C., methanesulfonyl chloride(13 ml) was added dropwise at the same temperature. After stirring for15 minutes at the same temperature, the mixture was heated to 0° C. andstirred for 30 minutes and then 2 hours at room temperature. After 0.1Nhydrochloric acid was added, and the mixture was diluted withdichloromethane, the resultant organic layer was separated, washed witha saturated aqueous solution of sodium hydrogencarbonate and saturatedsaline and dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure to obtain crude ethyl(1R*,3S*,4S*)-3-tert-butoxycarbonylamino-4-methanesulfonyloxycyclohexane-1-carboxylate.

[0686] The product obtained above was dissolved in N,N-dimethylformamide(100 ml), and sodium azide (18 g) was added at room temperature. Themixture was heated to 75° C. and stirred for 12 hours. The solvent wasconcentrated to about ⅓, and the residue was diluted with water andethyl acetate to conduct stirring for 3 minutes. The resultant organiclayer was separated, washed with saturated saline and dried overanhydrous magnesium sulfate. The solvent was distilled off under reducedpressure, and the residue was purified by column chromatography onsilica gel (ethyl acetate:hexane=1:4) to obtain the title compounds[(1R*,3S*,4R*)-form (6.74 g) and (1R*,3S*,4S*)-form (1.32 g)] ascolorless solids.

[0687] (1R*, 3S*, 4R*)-form: ¹H-NMR (CDCl₃) δ: 1.26(3H,t,J=7.1 Hz),1.45(9H,s), 1.38-2.33(6H,m), 2.57-2.68(1H,m), 3.77-4.20(4H,m),4.63(1H,br.s). (1R*,3S*,4S*)-form: ¹H-NMR (CDCl₃) δ: 1.27(3H,t,J=7.1Hz), 1.46(9H,s), 1.53-2.30(6H,m), 2.50-2.65(1H,m), 3.42-3.72(2H,m),4.15(2H,q,J=7.1 Hz), 4.67(1H,br.s).

Referential Example 158 (1R*,2S*,4R*)-N²-tert-Butoxycarbonyl-4-ethoxycarbonyl-1,2-cyclohexanediamine

[0688]

[0689] Ethyl(1R*,3S*,4R*)-4-azido-3-(tert-butoxycarbonylamino)cyclohexane-1-carboxylate(5.4 g) was dissolved in a mixed solvent of ethanol (10 ml) and ethylacetate (10 ml), and a catalytic amount of 10% palladium on carbon wasadded to stir the mixture at room temperature for 20 hours in a hydrogenatmosphere. After insoluble matter was removed by filtration, thesolvent was distilled off under reduced pressure to obtain the titlecompound (4.7 g) as a pale yellow oil.

Referential Example 159(1R*,2S*,4R*)-N²-tert-Butoxycarbonyl-N¹-[(5-chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-1,2-cyclohexanediamine

[0690]

[0691] (1R*,2S*,4R*)-N²-tert-Butoxycarbonyl-4-ethoxycarbonyl-1,2-cyclohexanediamine (4.62 g)was dissolved in dichloromethane (50 ml), 5-chloroindole-2-carboxylicacid (3.63 g), 1-hydroxybenzotriazole monohydrate (2.43 g) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.45 g)were added at room temperature, and the mixture was stirred for 12hours. After 0.1N hydrochloric acid was added, and the mixture wasextracted with dichloromethane, the resultant organic layer was washedwith a saturated aqueous solution of sodium hydrogencarbonate andsaturated saline and dried over anhydrous magnesium sulfate. The solventwas distilled off under reduced pressure, and the residue was purifiedby column chromatography on silica gel (ethyl acetate:hexane=2:3) toobtain the title compound (5.3 g) as a colorless solid.

[0692]¹H-NMR (CDCl₃) δ: 1.26(3H,t, J=7.1 Hz), 1.43 (9H,s),1.35-2.46(7H,m), 3.91-4.02(1H,m), 4.10-4.22(2H,m), 4.79(1H,br.s),6.79(1H,s), 7.18-7.40(2H,m), 7.59(1H,s), 8.00(1H,br.s), 9.13(1H,br.s).

Referential Example 160 (1R*,2R*,4S*)-N²-tert-Butoxycarbonyl-N¹-[(5-chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-1,2-cyclohexanediamine

[0693]

[0694] 1)(1R*,2R*,4S*)-N²-tert-Butoxycarbonyl-4-ethoxycarbonyl-1,2-cyclohexanediaminewas obtained from ethyl(1R*,3S*,4S*)-4-azido-3-(tert-butoxycarbonylamino)-cyclohexane-1-carboxylateobtained in Referential Example 157 in a similar manner to ReferentialExample 158.

[0695] 2) The title compound was obtained from the product describedabove in a similar manner to Referential Example 159.

[0696]¹H-NMR (CDCl₃) δ: 1.22-1.72(6H,m), 1.34(9H,3), 2.15-2.28(2H,m),2.41-2.49(1H,m), 2.85(1H,brs), 3.62-3.75(1H,m), 3.78-3.92(1H,m),4.12-4.28(2H,m), 4.56-4.63(1H,m), 6.88(1H,brs), 7.20(1H,dd,J=8.8 and 2.0Hz), 7.33(1H,d,J=8.8 Hz), 7.52-7.57(1H,m), 7.59(1H,d,J=2.0 Hz),9.24(1H,s). MS (ESI) m/z: 464(M+H)⁺.

Referential Example 161 Ethyl(1S,3S,4R)-3,4-epoxycyclohexane-1-carboxylate

[0697] (1S,4S,5S)-4-Iodo-6-oxabicyclo[3.2.1]octan-7-on (J. Org. Chem.,1996, Vol. 61, p. 8687) (89.3 g) was dissolved in ethanol (810 ml), a 2Naqueous solution (213 ml) of sodium hydroxide was added, and the mixturewas then stirred at room temperature for 3 hours. After the solvent wasdistilled off under reduced pressure, and water was added to the residueto conduct extraction with dichloromethane, the extract was dried overanhydrous magnesium sulfate. The solvent was distilled off under reducedpressure, and the residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=17:3) to obtain the title compound(41.2 g) as a pale yellow oil.

[0698] [α]_(D)−58° (C=1.0, chloroform).

Referential Example 162 Ethyl(1S,3R,4R)-3-azido-4-hydroxycyclohexane-1-carboxylate

[0699] Ethyl (1S,3S,4R)-3,4-epoxycyclohexane-1-carboxylate (41 g) wasdissolved in N,N-dimethylformamide (300 ml), ammonium chloride (19.3 g)and sodium azide (23.5 g) were successively added at room temperature,and the mixture was then stirred at 75° C. for 13 hours. The reactionmixture was filtered, the filtrate was concentrated to distill off 400ml of the solvent, the product captured by the filter was put in theresidue, and water was added to dissolve the collected product. Thesolution was extracted with ethyl acetate. The resultant organic layerwas washed with water and saturated saline and dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressureto obtain the title compound (51.5 g) as an oil.

[0700] [α]_(D)+8° (C=1.0, chloroform).

Referential Example 163 Ethyl(1S,3R,4R)-3-(tert-butoxycarbonylamino)-4-hydroxycyclohexane-1-carboxylate

[0701] Ethyl (1S,3R,4R)-3-azido-4-hydroxycyclohexane-1-carboxylate (51.2g) and di-tert-butyl dicarbonate (68.1 g) were dissolved in ethylacetate (1000 ml), and 5% palladium on carbon was added to stir themixture for 16 hours at room temperature under a hydrogen pressure of 5kg/cm². After insoluble matter was removed by filtration, the solventwas distilled off under reduced pressure, the residue was purified bycolumn chromatography on silica gel (hexane:ethyl acetate=4:1), andhexane was added to solidify it to obtain the title compound (53.6 g) ascolorless crystals.

[0702] [α]_(D)+25 (C=1.0, chloroform).

Referential Example 164 Ethyl(1S,3R,4S)-4-azido-3-(tert-butoxycarbonylamino)-cyclohexane-1-carboxylateand ethyl(1S,3R,4R)-4-azido-3-(tert-butoxycarbonylamino)cyclohexane-1-carboxylate

[0703] Ethyl(1S,3R,4R)-3-(tert-butoxycarbonylamino)-4-hydroxycyclohexane-1-carboxylate(53.5 g) and triethylamine (130 ml) were dissolved in dichloromethane(500 ml), and methanesulfonyl chloride (42 ml) was added dropwise whilecooling the solution to −10° C. to −15° C. After stirring for 20 minutesat the same temperature, the mixture was heated to room temperature over30 minutes and further stirred for 2 hours. The reaction mixture wascooled to 0° C., 0.5N hydrochloric acid (800 ml) was added dropwise, andthe mixture was extracted with dichloromethane. The resultant organiclayer was washed with a saturated aqueous solution of sodiumhydrogencarbonate and saturated saline and dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressureto obtain crude ethyl(1S,3R,4R)-3-(tert-butoxycarbonylamino)-4-(methanesulfonyloxy)cyclohexane-1-carboxylate.

[0704] The crude ethyl(1S,3R,4R)-3-(tert-butoxycarbonylamino)-4-(methanesulfonyloxy)cyclohexane-1-carboxylateobtained above was dissolved in N,N-dimethylformamide (335 ml), andsodium azide (60.5 g) was added to stir the mixture at 68 to 73° C. for16 hours. The reaction mixture was filtered, the filtrate wasconcentrated to distill off 250 ml of the solvent, the product capturedby the filter was put in the residue, and the collected product wasdissolved in water and extracted with ethyl acetate. The resultantorganic layer was washed with saturated saline and dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure,and the residue was purified by column chromatography on silica gel(ethyl acetate:hexane=1:4) to obtain the title compounds[(1S,3R,4S)-form (18.4 g) and (1S,3R,4R)-form (3.3 g)] as colorlesssolids.

[0705] (1S,3R,4S)-form: [α]_(D)+62° (C=1.0, chloroform) (1S,3R,4R)-form:[α]_(D)−19° (C=1.0, chloroform)

Referential Example 165(1S,2R,4S)-N²-tert-Butoxycarbonyl-4-ethoxycarbonyl-1,2-cyclohexanediamine

[0706] Ethyl(1S,3R,4S)-4-azido-3-(tert-butoxycarbonylamino)cyclohexane-1-carboxylate(4.0 g) was dissolved in a mixed solvent of ethanol (150 ml) and ethylacetate (150 ml), and 5% palladium on carbon (0.5 g) was added to stirthe mixture at room temperature for 17 hours in a hydrogen atmosphere.After insoluble matter was removed by filtration, the solvent wasdistilled off under reduced pressure to obtain the title compound (4.2g) as a pale yellow oil.

Referential Example 166(1S,2R,4S)-N²-tert-Butoxycarbonyl-N¹-[(5-chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-1,2-cyclohexanediamine

[0707](1S,3R,4S)-N²-tert-Butoxycarbonyl-4-ethoxycarbonyl-1,2-cyclohexanediamine(4.2 g) was dissolved in dichloromethane (50 ml),5-chloroindole-2-carboxylic acid (3.33 g), 1-hydroxybenzotriazolemonohydrate (2.52 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (3.15 g) were added at room temperature, and the mixturewas stirred for 12 hours. After 0.1N hydrochloric acid was added to thereaction mixture, and the mixture was extracted with dichloromethane,the resultant organic layer was washed with a saturated aqueous solutionof sodium hydrogencarbonate and saturated saline and dried overanhydrous magnesium sulfate. The solvent was distilled off under reducedpressure, and the residue was purified by column chromatography onsilica gel (ethyl acetate:hexane=1:1) to obtain the title compound (4.36g) as a colorless solid.

[0708] [α]_(D)−27° (C=1.0, chloroform)

Referential Example 167(1S,2R,4S)-N²-tert-Butoxycarbonyl-4-ethoxycarbonyl-N¹-[(5-fluoroindol-2-yl)carbonyl]-1,2-cyclohexanediamine

[0709]

[0710] Ethyl(1S,3R,4R)-4-azido-3-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylate(500 mg) was dissolved in methanol (10 ml), and 10% palladium on carbon(50 mg) was added to stir the mixture in a hydrogen atmosphere. After 3hours, the reaction was stopped to remove the catalyst by filtration,and the reaction mixture was concentrated under reduced pressure. Theresidue was dissolved in dichloromethane (10 ml) andN,N-dimethylformamide (10 ml), and 5-fluoroindole-2-carboxylic acid (345mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (460mg), 1-hydroxybenzotriazole monohydrate (325 mg) and N-methylmorpholine(485 mg) were added to stir the mixture at room temperature for 15hours. After the solvent was distilled off under reduced pressure,dichloromethane was added, and the resultant organic layer was washedwith a saturated aqueous solution of sodium hydrogencarbonate and driedover anhydrous magnesium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by column chromatographyon silica gel (methanol:dichloromethane=1:50) to obtain the titlecompound (740 mg) as a pale yellow amorphous substance.

[0711]¹H-NMR (CDCl₃) δ: 1.26(3H,t,J=7.1 Hz), 1.52(9H,s),1.67-2.41(7H,m), 3.97(1H,br.s), 4.15(2H,q,J=7.1 Hz), 4.08-4.22(1H,m),6.83(1H,s), 7.00-7.05(1H,m), 7.32-7.36(1H,m), 8.02(1H,s), 9.51(1H,s). MS(FAB) m/z: 448(M+H)⁺.

Referential Example 168(1R*,2S*,4R*)-N²-(tert-Butoxycarbonyl)-4-ethoxycarbonyl-N¹-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[0712]

[0713] The title compound was obtained from(1R*,2S*,4R*)-N²-tert-butoxycarbonyl-4-ethoxycarbonyl-1,2-cyclohexanediamineand lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in asimilar manner to Referential Example 48.

Referential Example 169 Benzyl (±)-3-cyclohexene-1-carboxylate

[0714]

[0715] (±)-3-Cyclohexene-1-carboxylic acid (50 g) was dissolved inN,N-dimethylformamide (550 ml), and triethylamine (170 ml) and benzylbromide (61 ml) were added under ice cooling to stir the mixture at roomtemperature for 12 hours. Water was added, extraction was conducted withethyl acetate, and the resultant organic layer was washed with saturatedsaline and then dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (hexane:ethyl acetate=3:1) to obtainthe title compound (70.8 g) as a reddish brown oil.

[0716]¹H-NMR (CDCl₃) δ: 1.66-1.76(1H,m), 2.00-2.13(3H,m),2.27-2.29(2H,m), 2.58-2.65(1H,m), 5.13(2H,s), 5.66(2H,br.s),7.29-7.38(5H,m).

Referential Example 170 Benzyl (1R*,3S*,4R*)-3,4-epoxycyclohexane-1-carboxylate

[0717]

[0718] Benzyl (±)-3-cyclohexene-1-carboxylate (40 g) was dissolved indichloromethane (500 ml), and m-chloroperbenzoic acid (86 g) was addedunder ice cooling to stir the mixture for 2 hours. After a 10% aqueoussolution of sodium thiosulfate was added to conduct stirring for 20minutes, an organic layer was separated, washed with a saturated aqueoussolution of sodium hydrogencarbonate and saturated saline and then driedover anhydrous magnesium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by column chromatographyon silica gel (ethyl acetate:hexane=1:9) to obtain the title compound(23.4 g) and benzyl (1R*,3R*,4S*)-3,4-epoxycyclohexane-1-carboxylate(12.1 g) as colorless oils.

[0719]¹H-NMR (CDCl₃) δ: 1.39-1.49(1H,m), 1.75-1.82(1H,m),1.90-2.04(3H,m), 2.30(1H,dd,J=14.9,4.9 Hz), 2.54-2.61(1H,m),3.12-3.14(1H,m), 3.22-3.24(1H,m), 5.12(2H,s), 7.30-7.39(5H,m). MS (FAB)m/z: 233(M+H)⁺.

Referential Example 171 Benzyl(1R*,3S*,4S*)-4-azido-3-hydroxycyclohexane-1-carboxylate

[0720]

[0721] Benzyl (1R*,3S* 4R*)-3,4-epoxycyclohexane-1-carboxylate (52.3 g)was dissolved in N,N-dimethylformamide (1000 ml), ammonium chloride(21.9 g) and sodium azide (18.1 g) were added, and the mixture washeated to 70° C. and stirred for 24 hours. The solvent was distilled offunder reduced pressure, and water was added to conduct extraction withethyl acetate. The resultant organic layer was washed with saturatedsaline and dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure to obtain the title compound (61.8g) as a colorless oil.

[0722]¹H-NMR (CDCl₃) δ: 1.51-1.66(2H,m), 1.91-1.98(1H,m),2.07-2.10(1H,m), 2.27-2.32(1H,m), 2.51-2.52(1H,m), 2.81-2.86(1H,m),3.30-3.36(1H,m), 3.70-3.75(1H,m), 5.13(2H,s), 7.30-7.39(5H,m).

Referential Example 172 Benzyl(1R*,3S*,4S*)-4-(N-tert-butoxycarbonyl)amino-3-hydoxycyclohexane-1-carboxylate

[0723]

[0724] Benzyl (1R*,3S*,4S*)-4-azido-3-hydroxycyclohexane-1-carboxylate(5.27 g) was dissolved in tetrahydrofuran (25 ml), andtriphenylphosphine (5.53 g) and water (0.55 ml) were added to stir themixture at room temperature for 20 hours. Di-tert-butyl dicarbonate(4.82 g) was added to the reaction mixture to continue stirring foradditional 2 hours. The solvent was distilled off under reducedpressure, and the residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=2:1) to obtain the title compound (6.22g) as a colorless oil.

[0725]¹H-NMR (CDCl₃) δ: 1.44(9H,s), 1.59-1.66(2H,m), 1.88-2.00(2H,m),2.29-2.32(1H,m), 2.80-2.85(1H,m), 3.02(1H,br.s), 3.42(1H,br.s),3.59-3.65(1H,m), 4.56(1H,br.s), 5.12(2H,q,J=12.5 Hz), 7.30-7.38(5H,m).MS (FAB) m/z: 350(M+H)⁺.

Referential Example 173 Methyl(1R*,3S*,4S*)-4-N-(tert-butoxycarbonylamino)-3-hydroxycyclohexane-1-carboxylate

[0726]

[0727] Benzyl(1R*,3S*,4S*)-4-N-(tert-butoxy-carbonylamino)-3-hydroxycyclohexane-1-carboxylate(2.54 g) was dissolved in ethyl acetate (15 ml), and a catalytic amountof 10% palladium on charcoal was added to the solution. The mixture wasstirred in a hydrogen stream at room temperature for 20 hours. After thecatalyst was filtered off, the filtrate was concentrated under reducedpressure to give(1R*,3S*,4S*)-4-N-(tert-butoxycarbonylamino)-3-hydroxycyclohexane-1-carboxylicacid as a colorless oil. The oil was dissolved in a mixture of methanol(8 ml) and toluene (15 ml), to which 2N trimethylsilyldiazomethanesolution (10 ml) was added, and the resulting mixture was stirred for 30minutes at room temperature. After removal of the solvent under reducedpressure, the resulting residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=1:1) to obtain the title compound (1.82g) as an colorless oil.

[0728]¹H-NMR (CDCl₃) δ: 1.44 (9H,s), 1.36-2.32(7H,m), 2.74-2.82 (1H,m),3.04 (1H,br.s), 3.33-3.47(1H,m), 3.55-3.65(1H,m), 3.68(3H,s),4.56(1H,br.s). MS (FAB) m/z: 274 (M+H)⁺.

Referential Example 174 Methyl(1R*,3R*,4S*)-3-azido-4-N-(tert-butoxycarbonylamino)cyclohexane-1-carboxylateand methyl(1R*,3R*,4R*)-3-azido-4-N-(tert-butoxycarbonyl-amino)cyclohexane-1-carboxylate

[0729]

[0730] Methyl (1R*,3S*,4S*)-4-(N-tert-butoxycarbonyl-amino)-3-hydroxycyclohexane-1-carboxylate(1.81 g) was dissolved in dichloromethane (36 ml), and triethylamine(4.6 ml) and methanesulfonyl chloride (1.63 ml) were added at −78° C.After 30 minutes, the mixture was heated to 0° C. and stirred for 30minutes. 1N Hydrochloric acid was added, extraction was conducted withdichloromethane, and the resultant organic layer was washed withsaturated saline and dried over anhydrous magnesium sulfate. The solventwas distilled off under reduced pressure to obtain crude methyl(1R*,3S*,4S*)-4-N-tert-butoxycarbonylamino-3-methanesulfonyloxycyclohexane-1-carboxylate.

[0731] The crude methyl(1R*,3S*,4S*)-4-N-tert-butoxycarbonylamino-3-methanesulfonyloxycyclohexane-1-carboxylatewas dissolved in N,N-dimethylformamide (23 ml), sodium azide (1.29 g)was added, and the mixture was heated to 70° C. and stirred for 12hours. Water was added to the reaction mixture, extraction was conductedwith ethyl acetate, and the resultant organic layer was washed withsaturated saline and dried over anhydrous magnesium sulfate. The solventwas distilled off under reduced pressure, and the residue was purifiedby flash column chromatography on silica gel (ethyl acetate:hexane=3:17)to obtain methyl(1R*,3R*,4R*)-3-azido-4-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylate(85 mg) and methyl(1R*,3R*,4S*)-3-azido-4-(N-tert-butoxy-carbonylamino)cyclohexane-1-carboxylate(590 mg) as colorless oils. (1R*,3R*,4S*)-form: ¹H-NMR (CDCl₃) δ:1.45(9H,s), 1.35-2.35(7H,m), 2.45-2.55(1H,m), 3.73(3H,s), 3.67-3.84(2H,m), 4.70(1H,br.s). MS (FAB) m/z: 299(M+H)⁺. (1R* ,3R*,4R*)-form:¹H-NMR (CDCl₃) δ: 1.45(9H,s), 1.56-2.25(7H,m), 2.68-2.80(1H,m),3.70(3H,s), 3.48-3.68(2H,m), 4.56(1H,br.s). MS (FAB) m/z: 299(M+H)⁺.

Referential Example 175(1R*,2S*,4S*)-N¹-tert-butoxycarbonyl-4-methoxycarbonyl-1,2-cyclohexanediamine

[0732]

[0733] Methyl(1R*,3R*,4S*)-3-azido-4-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylate(230 mg) was dissolved in ethyl acetate (8 ml), and a catalytic amountof 10% palladium on carbon was added to stir the mixture at roomtemperature for 20 hours in a hydrogen atmosphere. Insoluble matter wasremoved by filtration, and the filtrate was concentrated under reducedpressure to obtain the title compound (220 mg) as a pale yellow oil.

Referential Example 176(1R*,2S*,4S*)-N¹-tert-Butoxycarbonyl-4-methoxycarbonyl-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[0734]

[0735] The title compound was obtained from(1R*,2S*,4S*)-N¹-tert-butoxycarbonyl-4-methoxycarbonyl-1,2-cyclohexanediamineand lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in asimilar manner to Referential Example 48.

[0736]¹H-NMR (CDCl₃) δ: 1.46(9H,s), 1.53-1.95(5H,m), 2.17-2.24(1H,m),2.50(3H,s), 2.50-2.53(1H,m), 2.80-2.96(4H,m), 3.67(3H,s),3.69-3.74(1H,m), 4.10(2H,br.s), 4.88(1H,br.s). MS (FAB) m/z: 453(M+H)⁺.

Referential Example 177(1R*,2S*,4S*)-N¹-tert-Butoxycarbonyl-4-methoxycarbonyl-N²-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine

[0737]

[0738] The title compound was obtained from(1R*,2S*,4S*)-N¹-tert-butoxycarbonyl-4-methoxycarbonyl-1,2-cyclohexanediamineand 5-chloroindole-2-carboxylic acid in a similar manner to ReferentialExample 159.

[0739]¹H-NMR (CDCl₃) δ: 1.33(9H,s), 1.42-2.47(6H,m), 2.78-2.88(1H,m),3.70(3H,s), 3.86-4.15(2H,m), 4.65-4.75(1H,m), 6.86(1H,br.s),7.18-7.38(2H,m), 7.57-7.61(1H,m), 8.32(1H,br.s). MS (ESI) m/z:450(M+H)⁺.

Referential Example 178 Benzyl(1R,3S,4R)-3,4-epoxycyclohexane-1-carboxylate

[0740] 1) Benzyl (1R)-3-cyclohexene-1-carboxylate was obtained from(1R)-3-cyclohexene-1-carboxylic acid (J. Am. Chem. Soc., 1978, Vol. 100,p. 5199) in a similar manner to Referential Example 169.

[0741] 2) The title compound was obtained from the above-describedproduct in a similar manner to Referential Example 170.

[0742] MS (FAB) m/z: 233(M+H)⁺.

Referential Example 179 Benzyl(1R,3S,4S)-4-(N-tert-butoxycarbonylamino)-3-hydroxycyclohexane-1-carboxylate

[0743] 1) Benzyl (1R,3S,4S)-4-azido-3-hydroxycyclohexane-1-carboxylatewas obtained from benzyl (1R,3S,4R)-3,4-epoxycyclohexane-1-carboxylatein a similar manner to Referential Example 171.

[0744] 2) The title compound was obtained from the above-describedproduct in a similar manner to Referential Example 172.

[0745] MS (FAB) m/z: 350(M+H)⁺.

Referential Example 180 Benzyl(1R,3R,4S)-3-azido-4-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylate

[0746]

[0747] The title compound was obtained from benzyl(1R,3S,4S)-4-(N-tert-butoxycarbonylamino)-3-hydroxycyclohexane-1-carboxylatein a similar manner to Referential Example 174.

[0748]¹H-NMR (CDCl₃) δ: 1.45(9H,s), 1.52-1.66(2H,m), 1.83-2.01(3H,m),2.20-2.28(1H,m), 2.51-2.54(1H,m), 3.77(2H,br.s), 4.70(1H,br.s),5.15(2H,ABq,J=12.2 Hz), 7.33-7.38(5H,m). MS (FAB) m/z: 375(M+H)⁺.

Referential Example 181 Methyl(1R,3R,4S)-3-azido-4-(N-tert-butoxycarbonyl-amino)cyclohexane-1-carboxylate

[0749]

[0750] Benzyl(1R,3R,4S)-3-azido-4-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylate(3.5 g) was dissolved in tetrahydrofuran (130 ml) and water (16 ml), andlithium hydroxide (291 mg) was added under ice cooling. After 10minutes, the mixture was heated to room temperature to continuestirring. After 20 hours, the reaction was stopped, the solvent wasdistilled off under reduced pressure, and the resultant residue wassubjected to column chromatography on silica gel(methanol:dichloromethane=1:20) to obtain(1R,3R,4S)-3-azido-4-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylicacid (3.34 g) as a pale yellow oil. This product was dissolved inmethanol (18 ml) and toluene (64 ml), trimethylsilyldiazomethane (2 Msolution, 6.1 ml) was added under ice cooling, and the mixture washeated to room temperature and stirred. After 2 hours, the reaction wasstopped, the solvent was distilled off under reduced pressure, and theresidue was purified by column chromatography on silica gel (ethylacetate:hexane=1:4) to obtain the title compound (3.35 g) as a colorlessoil.

[0751]¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.57-1.63(2H,m), 1.82-1.85(1H,m),1.95-1.99(2H,m), 2.20-2.28(1H,m), 2.48-2.51(1H,m), 3.73(3H,s),3.78(2H,br.s), 4.70-4.72(1H,m). MS (FAB) m/z: 299(M+H)⁺.

Referential Example 182 (1S,2R,4R)-N¹-tert-Butoxycarbonyl-4-methoxycarbonyl-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[0752] 1)(1S,2R,4R)-N¹-tert-Butoxycarbonyl-4-methoxycarbonyl-1,2-cyclohexanediaminewas obtained from methyl(1R,3R,4S)-3-azido-4-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylatein a similar manner to Referential Example 175.

[0753] 2) The title compound was obtained from the above-describedproduct and lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in asimilar manner to Referential Example 176.

[0754] MS (FAB) m/z: 453(M+H)⁺.

Referential Example 183 Mixture of dimethyl(1R*,2S*,4S*,5R*)-4,5-dihydroxy-1,2-cyclohexanedicarboxylate anddimethyl (1R*,2S*,4R*,5S*)-4,5-dihydroxy-1,2-cyclohexanedicarboxylate

[0755]

[0756] Dimethyl (±)-cis-4-cyclohexene-1,2-dicarboxylate (20 g) wasdissolved in a mixed solvent of water (30 ml) and acetonitrile (90 ml),N-methylmorpholine N-oxide (18 g) and microcapsulated osmium (1.0 g)were added, and the mixture was stirred at room temperature for 17hours. After the reaction mixture was heated to 40° C. and stirred for 5hours, N-methylmorpholine N-oxide (11 g) was added, and the mixture wasstirred at 40° C. for 41 hours. The microcapsulated osmium was removedby filtration, and the filtrate was concentrated under reduced pressure.The residue was purified by column chromatography on silica gel(hexane:ethyl acetate=1:4), and the raw materials (5.0 g) were recoveredto obtain the title compound (6.2 g) as a colorless oil.

[0757]¹H-NMR (CDCl₃) δ: 2.09-2.13(4H,br.s), 3.13 (2H,br.s), 3.68(6H,s),3.90(2H, br.s) MS (FAB) m/z: 233(M+H)⁺.

Referential Example 184 Dimethyl (1R*,2S*,4R*,5S* or1R*,2S*,4S*,5R*)-4,5-diazido-1,2-cyclohexanedicarboxylate

[0758]

[0759] The title compound was obtained as a main product from a mixtureof dimethyl (1R*,2S*,4S*,5R*)-4,5-dihydroxy-1,2-cyclohexanedicarboxylateand dimethyl(1R*,2S*,4R*,5S*)-4,5-dihydroxy-1,2-cyclohexanedicarboxylate in asimilar manner to Referential Example 127.

[0760]¹H-NMR (CDCl₃) δ: 1.81-3.13(6H,m), 3.64-3.71(2H,m), 3.73 (6H,s)

Referential Example 185 Dimethyl (1R*,2S*,4R*,5S* or1R*,2S*,4S*,5R*)-4,5-bis-(tert-butoxycarbonylamino)-1,2-cyclohexanedicarboxylate

[0761]

[0762] Dimethyl (1R*,2S*,4R*,5S* or1R*,2S*,4S*,5R*)-4,5-diazido-1,2-cyclohexanedicarboxylate (900 mg) wasdissolved in tetrahydrofuran (100 ml), and di-tert-butyl dicarbonate (3g) and 10% palladium on carbon (180 mg) were added to stir the mixturefor 22 hours in a hydrogen atmosphere. After the catalyst was removed byfiltration, di-tert-butyl dicarbonate (1.5 g) and 10% palladium oncarbon (90 mg) were added to the filtrate to conduct a reaction for 5hours in a hydrogen atmosphere. The catalyst was removed by filtration,the filtrate was concentrated, the residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=1:1→2:3) to obtainthe title compound (570 mg) as white powder.

[0763]¹H-NMR (CDCl₃) δ: 1.44(18H,s), 2.08(4H,br.s), 2.87(2H,br.s),3.69(6H,s), 3.83(2H,br.s), 4.98(2H,br.s) MS (FAB) m/z: 431(M+H)⁺.

Referential Example 186(1R*,2S*,4R*)-N²-(tert-Butoxycarbonyl)-4-carbomoyl-N¹-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine

[0764]

[0765](1R*,2S*,4R*)-N²-(tert-Butoxycarbonyl)-N¹-[(5-chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-1,2-cyclohexanediamine(590 mg) was dissolved in a mixed solvent of ethanol (3 ml) andtetrahydrofuran (6 ml), a 1N aqueous solution (2.5 ml) of sodiumhydroxide was added at room temperature, and the mixture was stirred for12 hours. The solvent was distilled off to obtain the sodium salt of(1R*,2S*,4R*)-N²-(tert-butoxycarbonyl)-4-carboxy-N¹-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine.This product was suspended in N,N-dimethylformamide (4 ml),di-tert-butyl dicarbonate (654 mg) and ammonium hydrogencarbonate (1 g)were added at room temperature, and the mixture was stirred for 18hours. The solvent was distilled off under reduced pressure, and waterwas added to conduct extraction with chloroform. The resultant organiclayer was washed with saturated saline and dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure,and the residue was purified by column chromatography on silica gel(methylene chloride:methanol=47:3) to obtain the title compound (82 mg)as a colorless solid.

[0766] MS (ESI) m/z: 435(M+H)⁺.

Referential Example 187(1S,2R,4S)-N²-(tert-Butoxycarbonyl)-N¹-[(5-chloroindol-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamine

[0767]

[0768](1S,2R,4S)-N²-(tert-Butoxycarbonyl)-N¹-[(5-chloroindol-2-yl)carbonyl]-4-(ethoxycarbonyl)-1,2-cyclohexanediamine(1.5 g) was dissolved in tetrahydrofuran (10 ml) and ethanol (10 ml), a5N aqueous solution (1.29 ml) of sodium hydroxide was added, and themixture was stirred at room temperature for 18 hours. A 10% aqueoussolution of citric acid was added to the reaction mixture to weaklyacidify it. The reaction mixture was concentrated under reduced pressureand extracted with ethyl acetate, and the resultant organic layer waswashed with saturated saline and dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure, the residue wasdissolved in N,N-dimethylformamide (20 ml), and dimethylaminehydrochloride (791 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (806 mg), 1-hydroxybenzotriazole monohydrate (644 mg) andtriethylamine (2.24 ml) were added to stir the mixture at roomtemperature for 7 hours. Dimethylamine hydrochloride (527 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (620 mg),1-hydroxybenzotriazole monohydrate (495 mg) and triethylamine (896 ml)were additionally added, and the mixture was stirred at room temperaturefor 15 hours. The reaction mixture was concentrated, an aqueous solutionof sodium hydrogencarbonate was added to conduct extraction with ethylacetate, and the resultant organic layer was washed with a saturatedsaline and dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (dichloromethane:methanol=95:5) toobtain the title compound (1.49 g) as a pale yellow amorphous solid.

[0769]¹H-NMR (CDCl₃) δ: 1.52(9H,s), 1.71(1H,m), 1.89(2H,m), 2.13(1H,m),2.30(1H,m), 2.65(1H,s), 2.89(3H,s), 3.07(3H,s), 4.01(1H,br.s),4.20(1H,s), 4.82(1H,br.s), 6.79(1H,d,J=2.0 Hz), 7.23(1H,dd,J=8.5,2.0Hz), 7.35(1H,d,J=8.5 Hz), 7.59(1H,s), 8.02(1H,s), 9.54(1H,s). MS (ESI)m/z: 462(M+H)⁺.

Referential Example 188(1S,2R,4S)-1-Azido-2-(N-tert-butoxycarbonylamino)-4-[N-(tert-butyl)carbamoyl]cyclohexane

[0770]

[0771](1S,2R,4S)-1-Azido-2-(N-tert-butoxycarbonylamino)-4-methoxycarbonylcyclohexane(509 mg) was dissolved in tetrahydrofuran (40.0 ml), lithium hydroxide(111 mg) and water (5.0 ml) were successively added under ice cooling,and the mixture was stirred at room temperature for 36.5 hours. Thesolvent was distilled off under reduced pressure, water and 1Nhydrochloric acid (4.64 ml) were added to the residue, and the solventwas distilled off again under reduced pressure to obtain crude(1S,2R,4S)-1-azido-2-(N-tert-butoxycarbonylamino)-4-carboxycyclohexane.Dichloromethane (25 ml) and N,N-dimethylformamide (260 μl) were added tothis crude product, and the mixture was stirred under ice cooling.Further, oxalyl chloride (216 μl) was added to continuously stir themixture at room temperature for 1 hour. tert-Butylamine (1130 μl) wasadded to the reaction mixture under ice cooling to stir the mixture atroom temperature for 14 hours. After water and dichloromethane wereadded to the reaction mixture to conduct liquid separation, theresultant organic layer was dried over anhydrous sodium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by flash column chromatography on silica gel (hexane:ethylacetate=2:1) to obtain the title compound (197 mg) as a pale yellowamorphous substance.

[0772]¹H-NMR (CDCl₃) δ: 1.25-1.35(9H,m), 1.35-1.45(9H,m),1.55-2.00(6H,m), 2.20-2.30(1H,m), 3.70-4.80(3H,m), 5.30-5.45(1H,m).

[0773] MS (FAB) m/z: 340(M+H)⁺.

Referential Example 189(1S,2R,4S)-N²-(tert-butoxycarbonyl)-4-[N-(tert-butyl)carbamoyl]-1,2-cyclohexanediamine

[0774]

[0775] The title compound was obtained from(1S,2R,4S)-1-azido-2-(tert-butoxycarbonylamino)-4-[N-(tert-butyl)carbamoyl]cyclohexanein a similar manner to Referential Example 47.

[0776]¹H-NMR (CDCl₃) δ: 1.20-1.35(9H,m), 1.44(9H,s), 1.50-2.20(9H,m),2.90-3.00(1H,m), 3.84(1H,br), 4.94(1H,br), 5.34(1H,br).

Referential Example 190(1S,2R,4S)-N²-(tert-Butoxycarbonyl)-4-[N-(tert-butyl)carbamoyl]-N¹-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine

[0777]

[0778] The title compound was obtained from(1S,2R,4S)-N²-(tert-butoxycarbonyl)-4-[N-(tert-butyl)carbamoyl]-1,2-cyclohexanediamineand 5-chloroindole-2-carboxylic acid in a similar manner to ReferentialExample 159.

[0779]¹H-NMR (CDCl₃) δ: 1.33(9H,s), 1.35-2.30(16H,m), 3.90-4.05(1H,m),4.15-4.25(1H,m), 5.04(1H,br), 5.42(1H,br), 6.65-6.90(1H,m),7.19(1H,dd,J=8.8,1.7 Hz), 7.37(1H,d,J=8.8 Hz), 7.59(1H,br), 8.13(1H,br),10.51(1H,s).

[0780] MS (ESI) m/z: 491(M+H)⁺.

Referential Example 191(3R)-1-Benzyl-3-(tert-butyldiphenylsilyloxy)pyrrolidine

[0781]

[0782] (3R)-1-Benzyl-3-hydroxypyrrolidine (500 μl) and imidazole (466mg) were dissolved in N,N-dimethylformamide (15 ml),tert-butyldiphenylsilyl chloride (1.57 ml) was added under ice cooling,and the mixture was stirred at room temperature for 9 days. After thesolvent was distilled off under reduced pressure, and dichloromethaneand water were added to the residue to conduct liquid separation, theresultant organic layer was dried over anhydrous sodium sulfate, and thesolvent was distilled off under reduced pressure. The residue wassubjected to flash column chromatography on silica gel (hexane:ethylacetate=3:1) to obtain the title compound (1.27 g) as a yellow oil.

[0783]¹H-NMR (CDCl₃) δ: 1.05(9H,s), 1.70-1.85(1H,m), 1.90-2.00(1H,m),2.45-2.65(3H,m), 2.70-2.80(1H,m), 3.50-3.70(2H,m), 4.35-4.45(1H,m),7.20-7.45(11H,m), 7.60-7.70(4H,m).

[0784] MS (ESI) m/z: 416(M+H)⁺.

Referential Example 1921-Benzhydryl-3-(tert-butyldiphenylsilyloxy)azetidine

[0785]

[0786] The title compound was obtained from1-benzhydryl-3-hydroxyazetidine hydrochloride in a similar manner toReferential Example 191.

[0787]¹H-NMR (CDCl₃) δ: 1.01(9H,s), 2.90-3.00(2H,m), 3.40-3.50(2H,m),4.36(1H,s), 4.40-4.50(1H,m), 7.10-7.20(2H,m), 7.20-7.30(4H,m),7.30-7.40(10H,m), 7.55-7.65(4H,m) MS (ESI) m/z: 478(M+H)⁺.

Referential Example 193cis-N¹,N²-Bis(benzyloxycarbonyl)-4-cyclohexene-1,2-diamine

[0788]

[0789] 4-Cyclohexene-1,2-diamine hydrochloride (4.0 g) was dissolved ina mixed solvent of water (20 ml) and acetonitrile (20 ml), and benzylchloroformate (7.66 ml) and potassium carbonate (14.9 g) were added, andthe mixture was stirred at room temperature for 3 days. Water was pouredinto the reaction mixture to conduct extraction with methylene chloride,and the resultant organic layer was washed with saturated saline. Thesolvent was distilled off under reduced pressure, and the residue waspurified by column chromatography on silica gel (dichloromethane) toobtain the title compound (8.22 g) as a colorless solid.

[0790]¹H-NMR (CDCl₃) δ: 2.03(2H,m), 2.53(2H,d,J=17.1 Hz), 3.77(2H,m),5.03(2H,q,J=12.3 Hz), 5.09(2H,q,J=12.3 Hz), 5.59(2H,s), 7.32(10H,m). MS(ESI) m/z: 381(M+H)⁺.

Referential Example 194(1R*,2S*)-N¹,N²-Bis(benzyloxycarbonyl)-4-hydroxy-1,2-cyclohexanediamine

[0791]

[0792] cis-N¹,N²-Bis(benzyloxycarbonyl)-4-cyclohexene-1,2-diamine (10 g)was dissolved in absolute tetrahydrofuran (70 ml), borane-dimethylsulfide complex (7.4 ml) was added at 0° C., and the mixture wasgradually heated to room temperature and stirred for 14 hours. Ice wasadded to the reaction mixture to decompose excessive borane, and a 1Naqueous solution (80 ml) of sodium hydroxide and 30% aqueous hydrogenperoxide (80 ml) were added to stir the mixture for 1 hour. The reactionmixture was extracted with ethyl acetate, and the resultant organiclayer was washed with saturated saline and dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, and theresidue was purified by column chromatography on silica gel (ethylacetate:hexane=2:1) to obtain the title compound (9.2 g) as a colorlesswax.

[0793]¹H-NMR (CDCl₃) δ: 1.98(1H,m), 2.08(1H,m), 2.30(1H,m), 3.43(2H,m),3.73(1H,m), 5.06(6H,m), 7.32(10H,s). MS (ESI) m/z: 399(M+H)⁺.

Referential Example 195(±)-cis-N¹,N²-Bis(benzyloxycarbonyl)-4-oxo-1,2-cyclohexanediamine

[0794]

[0795] Dimethylsulfoxide (8.2 ml) was added to a solution of oxalylchloride (9.9 ml) in dichloromethane (90 ml) at −60° C., and a solutionof(1R*,2S*)-N¹,N²-bis(benzyloxycarbonyl)-4-hydroxy-1,2-cyclohexanediamine(9.2 g) in tetrahydrofuran (90 ml) was added to the mixture in oneportion. After 1 hour, the temperature of the mixture was raised to −40°C., and triethylamine (26 ml) was added in one portion. The mixture washeated to room temperature as it is, and stirred for 3 hours. Thereaction mixture was poured into water and extracted with methylenechloride. The resultant organic layer was washed with saturated salineand then dried over anhydrous sodium sulfate. The solvent was distilledoff under reduced pressure, and the residue was purified by columnchromatography on silica gel (ethyl acetate:hexane=1:1) to obtain thetitle compound (8.0 g) as a pale yellow solid.

[0796]¹H-NMR (CDCl₃) δ: 2.27-2.43(4H,m), 2.78(1H,dd,J=14.4,3.9 Hz),3.86(2H,m), 5.08(4H,m), 5.22(2H,m), 7.32(10H,m). MS (ESI) m/z:397(M+H)⁺.

Referential Example 196(±)-cis-N¹,N²-Bis(benzyloxycarbonyl)-4,4-dimethoxy-1,2-cyclohexanediamine

[0797]

[0798] (±)-cis-N¹,N²-Bis(benzyloxycarbonyl)-4-oxo-1,2-cyclohexanediamine(3.89 g) was dissolved in a mixed solvent of methanol (15 ml) andtetrahydrofuran (15 ml), 2,2-dimethoxypropane (10.7 ml) andp-toluenesulfonic acid (187 mg) were added, and the mixture was stirredat room temperature for 3 hours. The solvent was concentrated, and asaturated aqueous solution of sodium hydrogencarbonate was added toconduct extraction with ethyl acetate. After the resultant organic layerwas washed with saturated saline and dried over anhydrous sodiumsulfate, the solvent was distilled off under reduced pressure, and theresidue was purified by column chromatography on silica gel (ethylacetate:hexane=1:2) to obtain the title compound (3.54 g) as a colorlessamorphous solid.

[0799]¹H-NMR (CDCl₃) δ: 1.30-1.41(4H,m), 1.93(1H,m), 2.38(1H,m),3.19(6H,s), 3.46(1H,m), 3.59(1H,m), 5.03(2H,q,J=12.5 Hz),5.09(2H,q,J=12.5 Hz), 7.32(10H,s).

Referential Example 197(±)-cis-N¹-[5-Chloroindol-2-yl)carbonyl]-4,4-dimethoxy-1,2-cyclohexanediamineand(±)-cis-N²-[(5-chloroindol-2-yl)carbonyl]-4,4-dimethoxy-1,2-cyclohexanediamine:

[0800]

[0801](±)-cis-N¹,N²-Bis(benzyloxycarbonyl)-4,4-dimethoxy-1,2-cyclohexanediamine(1.45 g) was dissolved in methanol (12 ml), and 10% palladium on carbon(290 mg) was added to stir the mixture at room temperature for 20 hoursin a hydrogen atmosphere. 10% Palladium on carbon (290 mg) and methanol(10 ml) were additionally added to stir the mixture for 8 hours. Thereaction mixture was filtered through Celite, and mother liquor wasconcentrated, and the residue was dissolved in N,N-dimethylformamide (10ml). 5-Chloroindole-2-carboxylic acid (320 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodi-imide hydrochloride (377 mg),1-hydroxybenzotriazole monohydrate (301 mg) and N-methylmorpholine (360ml) were added, and the mixture was stirred at room temperature for 14hours. The reaction mixture was poured into an aqueous solution ofsodium hydrogencarbonate and extracted with ethyl acetate. The resultantorganic layer was washed with saturated saline and then dried overanhydrous sodium sulfate, the solvent was distilled off under reducedpressure, and the residue was isolated and purified by preparativethin-layer chromatography on silica gel (dichloromethane:methanol=93:7)to obtain (±)-cis-N¹ (orN²)-[(5-chloroindol-2-yl)carbonyl]-4,4-dimethoxy-1,2-cyclohexanediamine(98 mg) and (±)-cis-N²(orN¹)-[(5-chloroindol-2-yl)carbonyl]-4,4-dimethoxy-1,2-cyclohexanediamine(105 mg).

(±)-cis-N¹ (orN²)-[(5-Chloroindol-2-yl)carbonyl]-4,4-dimethoxy-1,2-cyclohexanediamine

[0802]¹H-NMR (CDCl₃) δ: 1.48(2H,m), 2.08(2H,m), 2.34(1H,d,J=13.1 Hz),2.78(1H,dt,J=2.9,13.1 Hz), 3.18(3H,s), 3.23(,3H,s), 3.76(1H,m),6.24(1H,d,J=8.3 Hz), 6.79(1H,s), 7.23(1H,dd,J=8.8,2.0 Hz),7.35(1H,d,J=8.8 Hz), 7.60(1H,d,J=8.8 Hz), 9.53(1H,br.s). MS (ESI) m/z:352(M+H)⁺.

(±)-cis-N²(orN¹)-[(5-Chloroindol-2-yl)carbonyl]-4,4-dimethoxy-1,2-cyclohexanediamine

[0803]¹H-NMR (CDCl₃) δ: 1.85(1H,m), 1.99(1H,m), 2.39(1H,br,J=13.2 Hz),2.88(1H,m), 3.26(10H,m), 4.00(1H,m), 6.77(1H,s), 7.23(1H,d,J=8.5 Hz),7.37(1H,d,J=8.5 Hz), 7.61(1H,s),9.49(1H,br.s). MS (ESI) m/z: 352(M+H)⁺.

Referential Example 198(±)-cis-N¹,N²-Bis(benzyloxycarbonyl)-4,4-(1,2-ethylenedioxy)-1,2-cyclohexanediamine

[0804]

[0805] (±)-cis-N¹,N²-Bis(benzyloxycarbonyl)-4-oxo-1,2-cyclohexanediamine(4.0 g) was dissolved in absolute tetrahydrofuran (30 ml), and ethyleneglycol (5.6 ml) and p-toluenesulfonic acid (192 mg) were added to stirthe mixture at room temperature for 17 hours. The reaction mixture waspoured into a saturated aqueous solution of sodium hydrogencarbonate andextracted with ethyl acetate. The resultant organic layer was washedwith saturated saline and then dried over anhydrous sodium sulfate, thesolvent was distilled off under reduced pressure, and the residue waspurified by column chromatography on silica gel (ethylacetate:hexane=1:1) to obtain the title compound (4.23 g) as a paleyellow solid.

[0806]¹H-NMR (CDCl₃) δ: 1.65-1.71(4H,m), 2.00(1H,m), 2.11(1H,m),3.49(1H,m), 3.73(1H,m), 3.93(4H,s), 5.03(2H,q,J=12.2 Hz),5.08(2H,q,J=12.2 Hz), 7.32(10H,s). MS (ESI) m/z: 441(M+H)⁺.

Referential Example 199(±)-cis-N¹-[(5-chloroindol-2-yl)carbonyl]-4,4-(1,2-ethylenedioxy)-1,2-cyclohexanediamineand(±)-cis-N²-[(5-chloroindol-2-yl)carbonyl]-4,4-(1,2-ethylenedioxy)-1,2-cyclohexanediamine

[0807]

[0808] (±)-cis-N¹ (orN²)-[(5-Chloroindol-2-yl)carbonyl]-4,4-(1,2-ethylenedioxy)-1,2-cyclohexanediamineand (±)-cis-N²(orN¹)-[(5-chloroindol-2-yl)carbonyl]-4,4-(1,2-ethylenedioxy)-1,2-cyclohexanediaminewere obtained from(±)-cis-N¹,N²-bis(benzyloxycarbonyl)-4,4-(1,2-ethylenedioxy)-1,2-cyclohexanediaminein a similar manner to Referential Example 197.

(±)-cis-N¹(orN²)-[(5-Chloroindol-2-yl)carbonyl]-4,4-(1,2-ethylenedioxy)-1,2-cyclohexanediamine

[0809]¹H-NMR (CDCl₃) δ: 1.68-1.81(4H,m), 2.11(2H,m),2.87(1H,td,J=3.9,11.2 Hz), 3.77(1H,m), 3.97(4H,s), 6.27(1H,d,J=7.6 Hz),6.80(1H,s), 7.24(1H,d,J=9.0 Hz), 7.35(1H,d,J=9.0 Hz), 7.61(1H,s),9.47(br.s,1H). MS (ESI) m/z: 350(M+H)⁺.

(±)-cis-N²(orN¹)-[(5-Chloroindol-2-yl)carbonyl]-4,4-(1,2-ethylenedioxy)-1,2-cyclohexanediamine

[0810]¹H-NMR (CDCl₃) δ: 1.65(2H,m), 1.88(1H,m), 1.96(1H,m),2.31(1H,dd,J=12.9,3.2 Hz), 2.96(1H,m), 3.98(1H,m), 4.02(4H,s),4.12(1H,m), 6.77(1H,s), 7.06(1H,br.s), 7.23(1H,dd,J=8.8,2.0 Hz),7.37(1H,d,J=8.8 Hz), 7.62(1H,d, J=2.0 Hz), 9.49(1H,br.s). MS (ESI) m/z:350(M+H)⁺.

Referential Example 200cis-N¹,N²-Bis(tert-butoxycarbonyl)-4-cyclohexene-1,2-diamine

[0811]

[0812] cis-4-Cyclohexene-1,2-diamine hydrochloride (4.0 g) was dissolvedin a mixed solvent of water (40 ml) and acetonitrile (40 ml), anddi-tert-butoxy carbonate (11.8 g) and triethylamine (12 ml) were added,and the mixture was stirred at room temperature for 4.5 hours. Thereaction mixture was poured into water to conduct extraction withdichloromethane, and the resultant dichloromethane layer was washed withsaturated saline and then dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure, and the residue waspurified by column chromatography on silica gel (ethylacetate:hexane=1:4) to obtain the title compound (6.12 g) as a colorlesssolid.

[0813]¹H-NMR (CDCl₃) δ: 1.44(18H,s), 1.98(2H,dd,J=9.3,15.9 Hz),2.48(2H,br.d,J=15.9 Hz), 3.66(2H,br.s), 4.88(2H,br.s), 5.58(2H,d,J=2.7Hz).

Referential Example 201(1R*,2S*)-N¹,N²-Bis(tert-butoxycarbonyl)-4-hydroxy-1,2-cyclohexanediamine(mixture of stereoisomers)

[0814]

[0815] cis-N¹,N²-Bis (tert-butoxycarbonyl)-4-cyclohexene-1,2-diamine(6.1 g) was dissolved in absolute tetrahydrofuran (40 ml), andborane-dimethyl sulfide complex (2.22 ml) was added by a syringe underice cooling. The mixture was stirred for 16 hours while graduallyheating the mixture to room temperature as it is. Ice was added to thereaction mixture, and a 1N aqueous solution of sodium hydroxide and 30%aqueous hydrogen peroxide (50 ml) were added to stir the mixture at roomtemperature for 2 hours as it is. The reaction mixture was extractedwith ethyl acetate, and the resultant organic layer was washed withsaturated saline and dried over anhydrous sodium sulfate. The solventwas distilled off under reduced pressure, and the residue was purifiedby column chromatography on silica gel (ethyl acetate:hexane=1:2→2:1) toobtain the title compound (6.1 g) as a colorless oil.

[0816]¹H-NMR (CDCl₃) δ: 1.42(9H,s), 1.43(9H,s), 1.83-1.67(5H,m),2.15(1H,m), 2.22(1H,s), 3.34(1H,m), 3.78(1H,m), 4.15(1H,s),4.98(1H,q,J=9.0 Hz), 5.02(1H,q,J=9.0 Hz). MS (ESI) m/z: 331(M+H)⁺.

Referential Example 202cis-N¹,N²-Bis(tert-butoxycarbonyl)-4-oxo-1,2-cyclohexanediamine

[0817]

[0818] Dimethylsulfoxide (6.8 ml) was added to a solution of oxalylchloride (8.2 ml) in dichloromethane (100 ml) at −60° C., and a solutionof(1R*,2S*)-N¹,N²N-bis(tert-butoxycarbonyl)-4-hydroxy-1,2-cyclohexanediamine(mixture of stereoisomers) (6.32 g) in tetrahydrofuran (80 ml) was addedat a time, and the mixture was stirred for 1 hour. The temperature ofthe mixture was raised to −40° C., and triethylamine (21 ml) was added.The mixture was heated to room temperature. After 3 hours, the reactionmixture was poured into water and extracted with dichloromethane. Theresultant organic layer was washed with saturated saline and then driedover anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by column chromatographyon silica gel (ethyl acetate:hexane=1:1) to obtain the title compound(3.8 g) as a pale yellow solid.

[0819]¹H-NMR (CDCl₃) δ: 1.43(9H,s), 1.44(9H,s), 2.36-2.24(3H,)m,2.39-2.44(2H,m), 2.75(1H,dd,J=14.6,2.9 Hz), 3.66-3.81(2H,m),4.95-4.90(1H,m), 4.97-5.03(1H,m). MS (ESI) m/z: 329(M+H)⁺.

Referential Example 203(±)-cis-N¹,N²-Bis(tert-butoxycarbonyl)-4-methoxyimino-1,2-cyclohexanediamine

[0820]

[0821] cis-N¹,N²-Bis(tert-butoxycarbonyl)-4-oxo-1,2-cyclohexanediamine(1.5 g) was dissolved in methanol (30 ml), and O-methylhydroxylaminehydrochloride (572 mg) and pyridine (737 ml) were added to stir themixture at room temperature for 17 hours. After the reaction mixture wasconcentrated, water was added to conduct extraction with ethyl acetate.The resultant organic layer was washed with saturated saline and thendried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by column chromatographyon silica gel (ethyl acetate:hexane=1:4) to obtain the title compound(1.52 g) as a colorless solid.

[0822]¹H-NMR (CDCl₃) δ: 1.44(18H,s), 1.64(1H,m), 2.16(2H,m), 2.44(1H,m),3.45-3.63(3H,m), 3.82(3H,s), 4.93(1H,m). MS (ESI) m/z: 358(M+H)⁺.

Referential Example 204 (1R*,2S*,4R*(or4S*))-N¹,N²-Bis(tert-butoxycarbonyl)-4-tert-butyldiphenylsilyloxy-1,2-cyclohexanediamine(Stereoisomer A)

[0823]

[0824] The title compound was obtained from(1R*,2S*)-N¹,N²-bis(tert-butoxycarbonyl)-4-hydroxy-1,2-cyclohexanediamine(mixture of stereoisomers) in a similar manner to Referential Example191.

[0825]¹H-NMR (CDCl₃) δ: 1.03(9H,s), 1.39(9H,s), 1.40(9H,s), 1.72(1H,m),1.86(1H,m), 2.13(1H,m), 3.24(2H,m), 3.65(1H,m), 4.83(1H,m), 7.37(10H,m).

Referential Example 205(1R*,2S*)-4-Acetoxy-N¹,N²-bis(tert-butoxycarbonyl)-1,2-cyclohexanediamine(Stereoisomer B)

[0826]

[0827] (1R*,2S*)-N¹,N²-Bis(tert-butoxycarbonyl)-4-hydroxy-1,2-cyclohexanediamine(Stereoisomer B) (1.74 g) was dissolved in pyridine (15 ml), and aceticanhydride (5 ml) was added to stir the mixture at room temperature for 4days. 1N Hydrochloric acid was added to the reaction mixture, extractionwas conducted with ethyl acetate, and the resultant organic layer wassuccessively washed with 1N hydrochloric acid, a saturated aqueoussolution of sodium hydrogencarbonate and saturated saline, and thendried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by column chromatographyon silica gel (ethyl acetate:hexane=1:3) to obtain the title compound(1.96 g) as a colorless oil.

[0828]¹H-NMR (CDCl₃) δ: 1.43(18H,s), 1.89(2H,m), 2.10(3H,s), 2.19(1H,m),3.35(1H,m), 3.69(1H,m), 4.86(1H,d,J=8.3 Hz), 5.00(1H,d,J=8.3 Hz),5.11(1H,s). MS (ESI) m/z: 373(M+H)⁺.

Referential Example 206(1R*,2S*)-N¹,N²-Bis(benzyloxycarbonyl)-4-hydroxy-4-methyl-1,2-cyclohexanediamine

[0829]

[0830] Anhydrous cerium chloride (6.4 g) was suspended intetrahydrofuran (50 ml), and the suspension was cooled to −78° C. in anargon atmosphere. A methyllithium solution (1.14N diethyl ethersolution, 22.5 ml) was added to the suspension, and the mixture wasstirred at −78° C. for 30 minutes. A tetrahydrofuran solution (50 ml) of(±)-cis-N¹,N²-bis(benzyloxycarbonyl)-4-oxo-1,2-cyclohexanediamine (3.0g) was added dropwise at −78° C., and the mixture was stirred for 30minutes. The reaction mixture was poured into a 3% aqueous solution (100ml) of acetic acid, and diethyl ether (50 ml) was added to stir themixture at room temperature for 10 minutes. The reaction mixture wasextracted with ethyl acetate, and the resultant organic layer was washedwith a saturated aqueous solution of sodium hydrogencarbonate andsaturated saline and then dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure, and the residue waspurified twice by medium-pressure column chromatography on silica gel(methanol:chloroform=0:100-1:19) to obtain the title compound(Stereoisomer A) (780 mg) as a colorless foamy compound and the titlecompound (Stereoisomer B) (1.1 g) as white powder.

[0831] Stereoisomer A:

[0832]¹H-NMR (CDCl₃) δ: 1.26(3H,s), 1.27-2.08(6H,m), 3.48(1H,br.s),3.59(1H,br.s), 5.02-5.09(5H,m), 5.33(1H,br.s), 7.30-7.32(10H,s) MS (FAB)m/z: 413(M+H)⁺.

[0833] Stereoisomer B:

[0834]¹H-NMR (CDCl₃) δ: 1.25(3H,s), 1.29-2.07(6H,m), 3.39(1H,br.s),3.82(1H,br.s), 5.02-5.23(6H,m), 7.30(10H,s) MS(FAB) m/z: 413(M+H)⁺.

Referential Example 207 (1R* ,2S*)-4-Hydroxy-4-methyl-1,2-cyclohexanediamine (Stereoisomer A)

[0835]

[0836] 10% Palladium on carbon (350 mg) was suspended in a methanolsolution (100 ml) of(1R*,2S*)-N¹,N²-bis(benzyloxycarbonyl)-4-hydroxy-4-methyl-1,2-cyclohexanediamine(Stereoisomer A) (780 mg), and the suspension was stirred for 5 hours ina hydrogen atmosphere. The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure. After the residue wasdissolved in dichloromethane (100 ml), and the solution was dried overanhydrous sodium sulfate, the solvent was distilled off to obtain thetitle compound (Stereoisomer A) (190 mg) as a colorless oil.

[0837]¹H-NMR (CDCl₃) δ: 1.22(3H,s), 1.25-2.48(11H,m), 2.62(1H,br.s),2.78(1H,br.s).

Referential Example 208(1R*,2S*)-4-Hydroxy-4-methyl-1,2-cyclohexanediamine (Stereoisomer B)

[0838]

[0839] The title compound was obtained from(1R*,2S*)-N¹,N²-bis(benzyloxycarbonyl)-4-hydroxy-4-methyl-1,2-cyclohexanediamine(Stereoisomer B) in a similar manner to Referential Example 207.

[0840]¹H-NMR (CDCl₃) δ: 1.17(3H,s), 1.39-1.79(11H,m), 2.10-2.18(1H,m),2.55-2.61(1H,m)

Referential Example 209 Mixture of(1R*,2S*)-N¹-[(5-chloroindol-2-yl)carbonyl]-4-hydroxy-4-methyl-1,2-cyclohexanediamine(Stereoisomer A) and(1R*,2S*)-N²-[(5-chloroindol-2-yl)carbonyl]-4-hydroxy-4-methyl-1,2-cyclohexanediamine(Stereoisomer A)

[0841] The title compound was obtained from(1R*,2S*)-4-hydroxy-4-methyl-1,2-cyclohexanediamine (Stereoisomer A) and5-chloroindole-2-carboxylic acid in a similar manner to ReferentialExample 30.

[0842]¹H-NMR (CDCl₃) δ: 1.32(3H,s), 1.34-2.29(6H,m), 4.42-4.70(4H,br),7.13(2H,s), 7.50(2H,s), 8.00(1H,s), 11.0(1H,br)

Referential Example 210 (1R*,2S*)-N¹(orN²)-[(5-chloroindol-2-yl)carbonyl]-4-hydroxy-4-methyl-1,2-cyclohexanediamine(Stereoisomer B)

[0843] The title compound was obtained from(1R*,2S*)-4-hydroxy-4-methyl-1,2-cyclohexanediamine (Stereoisomer B) and5-chloroindole-2-carboxylic acid in a similar manner to ReferentialExample 125.

[0844]¹H-NMR (DMSO-d₆) δ: 1.18(3H,s), 1.23-1.96(6H,m), 4.12-5.60(4H,br),7.11-8.59(5H,m), 11.8(1H,br) MS (FAB) m/z: 322(M+H)⁺.

Referential Example 211(1R*,2S*)-4-(tert-Butyldiphenylsilyloxymethyl)-1,2-cyclohexanediol

[0845]

[0846] 1) 3-Cyclohexene-1-methanol (5.0 g) was dissolved inN,N-dimethylformamide (50 ml), and imidazole (3.93 g) andtert-butylchlorodiphenylsilane (14 ml) were added to stir the mixturefor 22 hours. After adding methanol, the solvent was distilled off underreduced pressure, and water was added to the residue to conductextraction with ethyl acetate. The extract was dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure,and the residue was purified by column chromatography on silica gel(hexane:ethyl acetate=30:1) to obtain(±)-4-(tert-butyldiphenylsilyloxymethyl)-1-cyclohexene (16.1 g) as acolorless oil.

[0847]¹H-NMR (CDCl₃) δ: 1.05(9H,s), 1.20-1.35(2H,m), 1.70-1.90(3H,m),2.05-2.20(2H,m), 3.55(2H,d,J=5.9 Hz), 5.67(2H,s), 7.35-7.50(6H,m),7.65-7.75(4H,m). MS (FAB) m/z: 351(M+H)⁺.

[0848] 2) The title compound was obtained from(±)-4-(tert-butyldiphenylsilyloxymethyl)-1-cyclohexene in a similarmanner to Referential Example 183.

[0849]¹H-NMR (CDCl₃)δ: 1.04, 1.05(total 9H,each s), 1.29-2.09(7H,m),2.05(2H,s), 3.44-3.51(2H,m), 3.52-3.67(1H,m), 4.00,3.96(total 1H,eachbr.s), 7.35-7.44(6H,m), 7.63-7.66(4H,m). MS (FAB) m/z: 385(M+H)⁺.

Referential Example 212(1R*,2S*)-4-(tert-Butyldiphenylsilyloxymethyl)-1,2-bis(methanesulfonyloxy)cyclohexane

[0850]

[0851] Methanesuflonyl chloride (2.5 ml) was added dropwise to adichloromethane solution (300 ml) of(1R*,2S*)-4-(tert-butyldiphenylsilyloxymethyl)-1,2-cyclohexanediol (4.2g) and triethylamine (9.1 ml) at 0° C., and the mixture was stirred for1.5 hours. Water was added to conduct extraction with dichloromethane,and the resultant organic layer was washed with a saturated aqueoussolution of sodium hydrogencarbonate and saturated saline and then driedover anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by medium-pressure columnchromatography on silica gel (hexane:ethyl acetate 3:2) to obtain thetitle compound (4.9 g) as a pale yellow oil.

[0852]¹H-NMR (CDCl₃) δ: 1.04, 1.05(total 9H,each s), 1.31-2.29(7H,m),3.07,3.08(total 3H,each s), 3.09,3.10(total 3H,each s),4.11(2H,dt,J=7.1,0.73 Hz), 4.65-4.72(1H,m), 5.11,5.08(total 1H,eachbr.s), 7.39-7.43(6H,m), 7.61-7.64(4H,m).

Referential Example 213 (1R*,2S*,)-4-(tert-Butyldiphenylsilyloxymethyl)-1,2-diazidocyclohexane(Stereoisomer A and Stereoisomer B)

[0853]

[0854] The respective title compounds (Stereoisomer A and StereoisomerB) were obtained from(1R*,2S*)-4-(tert-butyldiphenylsilyloxymethyl)-1,2-bis(methanesulfonyloxy)cyclohexanein a similar manner to Referential Example 127.

[0855] Stereoisomer A:

[0856]¹H-NMR (CDCl₃) δ: 0.88(1H,m), 1.06(9H,s), 1.24-1.30(2H,m),1.63-1.66(1H,m), 1.89-1.92(2H,m), 2.00-2.05(1H,m), 3.37-3.42(1H,m),3.52(2H,br.t,J=6.0 Hz), 3.92(1H,br.s), 7.37-7.45(6H,m), 7.63-7.65(4H,m).

[0857] Stereoisomer B:

[0858]¹H-NMR (CDCl₃) δ: 0.88(1H,m), 1.05(9H,s), 1.13-1.43(2H,m),1.79-1.84(3H,m), 2.02-2.06(1H,m), 3.34-3.38(1H,m), 3.47-3.51(2H,m),3.94(1H,br.d,J=2.9 Hz), 7.37-7.45(6H,m), 7.62-7.64(4H,m)

Referential Example 214(1R*,2S*)-4-(tert-Butyldiphenylsilyloxymethyl)-1,2-cyclohexanediamine(Stereoisomer A)

[0859]

[0860] The title compounds was obtained from(1R*,2S*)-4-(tert-butyldiphenylsilyloxymethyl)-1,2-diazidocyclohexane(Stereoisomer A) in a similar manner to Referential Example 128.

[0861]¹H-NMR (CDCl₃) δ: 1.05(9H,s), 1.09-1.76(7H,m), 2.76-2.79(1H,m),2.98(1H,br.s), 3.48-3.49(2H,m), 7.36-7.41(6H,m), 7.64-7.66(4H,m).

Referential Example 215(1R*,2S*)-4-tert-Butyldiphenylsilyloxymethyl-1,2-cyclohexanediamine(Stereoisomer B)

[0862]

[0863] The title compounds was obtained from(1R*,2S*)-4-(tert-butyldiphenylsilyloxymethyl)-1,2-diazidocyclohexane(Stereoisomer B) in a similar manner to Referential Example 128.

[0864]¹H-NMR (CDCl₃) δ: 1.05(9H,s), 1.42-1.79(7H,m), 2.70-2.73(1H,m),3.01-3.03(1H,m), 3.44-3.49(2H,m), 7.37-7.42(6H,m), 7.64-7.66(4H,m)

Referential Example 216(1R,3S,4S)-3-Azido-4-(N-tert-butoxycarbonyl-amino)cyclohexane-1-carboxylicacid

[0865]

[0866] Benzyl(1R,3S,4S)-3-azido-4-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylate(4.4 g) was dissolved in tetrahydrofuran (160 ml) and water (20 ml), andlithium hydroxide (366 mg) was added under ice cooling. After 10minutes, the mixture was heated to room temperature to continuestirring. After 20 hours, the solvent was distilled off under reducedpressure, and the residue was purified by column chromatography onsilica gel (methanol:dichloromethane=1:10) to obtain the title compound(1.86 g) as a pale yellow oil.

[0867]¹H-NMR (CDCl₃) δ: 1.47(9H,s), 1.72-1.73(2H,m), 1.82-1.90(3H,m),2.05-2.10(1H,m), 2.77-2.80(1H,m), 3.49-3.65(2H,m). MS (FAB)m/z:285(M+H)⁺.

Referential Example 217(1R,3S,4S)-3-Azido-4-(N-tert-butoxycarbonylamino)-1-(hydroxymethyl)cyclohexane

[0868]

[0869](1R,3S,4S)-3-Azido-4-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylicacid (1.86 g) was dissolved in dimethoxyethane (20 ml), and to thesolution isobutyl chloroformate (1.02 ml) and N-methylmorpholine (860mg) were added at −15° C. The mixture was stirred for 10 minutes at thesame temperature. The hydrochloride of N-morpholine deposited wasseparated by filtration, and an aqueous solution (4 ml) of sodiumborohydride (370 mg) was added to the filtrate to stir the mixture for10 minutes. After water was added, and the solvent was distilled offunder reduced pressure, the residue was extracted with dichloromethaneand dried over anhydrous magnesium sulfate. The solvent was distilledoff under reduced pressure, and the residue was purified by columnchromatography on silica gel (ethyl acetate:hexane=1:1) to obtain thetitle compound (1.35 g) as a colorless oil.

[0870]¹H-NMR (CDCl₃) δ: 1.46(9H,s), 1.33-2.20(7H,m), 3.52-3.55(2H,m),3.64-3.81(2H,m). MS(FAB) m/z: 271(M+H)⁺.

Referential Example 218(1R,3S,4S)-3-Azido-4-(N-tert-butoxycarbonylamino)-1-(tert-butyldiphenylsilyloxymethyl)cyclohexane

[0871]

[0872] The title compounds was obtained from(1R,3S,4S)-3-azido-4-(N-tert-butoxycarbonylamino)-1-(hydroxymethyl)cyclohexanein a similar manner to Referential Example 107.

[0873]¹H-NMR (CDCl₃) δ: 1.06(9H,s), 1.45(9H,s), 1.53-2.16(7H,m),3.51(2H,d,J=6.4 Hz), 3.61(2H,br.s), 7.36-7.46(6H,m), 7.63-7.66(4H,m).MS(FAB) m/z: 509(M+H)⁺.

Referential Example 219(1S,2S,4R)-N¹-tert-Butoxycarbonyl-4-(tert-butyldiphenylsilyloxymethyl)-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[0874]

[0875] 1)(1R,3S,4S)-3-Azido-4-(N-tert-butoxycarbonyl-amino)-1-(tert-butyldiphenylsilyloxymethyl)cyclohexane(2.59 g) was dissolved in methanol (50 ml), and 10% palladium on carbon(200 mg) was added to stir the mixture for 20 hours in a hydrogenatmosphere. After the catalyst was removed by filtration, the solventwas distilled off under reduced pressure, and the residue was purifiedby column chromatography on silica gel(methanol:dichloromethane=1:20→1:10) to obtain(1S,2S,4R)-N¹-tert-butoxycarbonyl-4-(tert-butyldiphenylsilyloxymethyl)-1,2-cyclohexanediamine(1.66 g) as a pale yellow oil.

[0876] 2) The title compound was obtained from(1S,2S,4R)-N¹-tert-butoxycarbonyl-4-(tert-butyldiphenyl-silyloxymethyl)-1,2-cyclohexanediamineand lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in asimilar manner to Referential Example 48.

[0877]¹H-NMR (CDCl₃) δ: 1.05(9H,s), 1.29(9H,s), 1.56-1.58(3H,m),1.80-1.84(2H,m), 2.00-2.05(2H,m), 2.49(3H,s), 2.80-2.81(2H,m),2.90-3.00(2H,m), 3.48(1H,br.s), 3.58-3.69(4H,m), 3.84(1H,br.s),7.35-7.44(6H,m), 7.63-7.65 (4H,m). MS (FAB) m/z: 663(M+H)⁺.

Referential Example 220(1S,2S,4R)-N¹-tert-Butoxycarbonyl-4-hydroxymethyl-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[0878]

[0879](1S,2S,4R)-N¹-tert-Butoxycarbonyl-4-(tert-butyldiphenylsilyloxymethyl)-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(1.25 g) was dissolved in tetrahydrofuran (30 ml), andtetrabutylammonium fluoride (1 M solution, 2.5 ml), and the mixture wasstirred at room temperature for 3 days. After the solvent was distilledoff under reduced pressure, dichloromethane was added, and the reactionmixture was washed with water, the resultant organic layer was driedover anhydrous magnesium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by column chromatographyon silica gel (methanol:dichloromethane=1:20-1:10) to obtain the titlecompound (540 mg) as a pale yellow amorphous substance.

[0880]¹H-NMR (CDCl₃) δ: 1.31(9H,s), 1.37-2.37(7H,m), 2.50(3H,s),2.76-2.82(2H,m), 2.89-2.98(2H,m), 3.56-3.75(5H,m), 3.91-3.94(1H,m),4.80-4.82(1H,m). MS (FAB) m/z: 425(M+H)⁺.

Referential Example 221(1R*,2R*,4S*)-N²(tert-Butoxycarbonyl)-N-¹[(5-chloroindol-2-yl)carbonyl]-4-hydroxymethyl-1,2-cyclohexanediamine

[0881]

[0882](1R*,2R*,4S*)-N²-(tert-Butoxycarbonyl)-N¹-[(5-chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-1,2-cyclohexanediamine(735 mg) was dissolved in dichloromethane (10 ml), a 1N hexane solution(5 ml) of isobutyllithium hydride was added at −78° C., and the mixturewas stirred for 3 hours and then 30 minutes at 0° C. A saturated aqueoussolution of ammonium chloride was added at −78° C., the mixture wasextracted with dichloromethane, and the resultant organic layer waswashed with a saturated aqueous solution of sodium bicarbonate andsaturated saline and then dried over anhydrous magnesium sulfate. Thesolvent was distilled off under reduced pressure, and the residue waspurified by column chromatography on silica gel(dichloromethane:methanol=19:1) to obtain the title compound (480 mg) asa colorless solid.

[0883]¹H-NMR (CDCl₃) δ: 1.20-2.30(7H,m), 3.60-3.86(4H,m), 4.64(1H,br.s),6.87(1H,s), 7.20-7.48(3H,m), 9.15(1H,br.s). MS(ESI) m/z: 422(M+H)⁺.

Referential Example 222(1R,2R,4S)-N²-(tert-Butoxycarbonyl)-N¹-[(5-chloroindol-2-yl)carbonyl]-4-hydroxymethyl-1,2-cyclohexanediamine

[0884]

[0885] The title compound was obtained from(1R,2R,4S)-N²-(tert-butoxycarbonyl)-N¹-[(5-chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-1,2-cyclohexanediaminein a similar manner to Referential Example 221.

[0886] MS(ESI) m/z:. 422(M+H)⁺.

Referential Example 223(1R*,2S*,4R*)-N²-tert-Butoxycarbonyl-N¹-[(5-chloroindol-2-yl)carbonyl]-4-(1-hydroxy-1-methylethyl)-1,2-cyclohexanidiamine

[0887]

[0888] Methyllithium (1.14N solution, 2.27 ml) was added to atetrahydrofuran solution (10 ml) of(1R*,2S*,4R*)-N²-tert-butoxycarbonyl-N¹-[(5-chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-1,2-cyclohexanediamine(200 mg) at −78° C., and the mixture was stirred for 1 hour and then 2hours under ice cooling. An aqueous solution of ammonium chloride wasadded to the reaction mixture to extract the reaction mixture withchloroform, and the resultant organic layer was washed with saturatedsaline and then dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (hexane:ethyl acetate=1:3) to obtainthe title compound (115 mg) as a colorless solid.

[0889]¹H-NMR (DMSO-d₆) δ: 1.04(6H,s), 1.33(9H,s), 0.97-2.05(7H,m),3.80-4.02(2H,m), 6.43(1H,m), 7.01(1H,br.s), 7.16(1H,brd,J=8.8 Hz),7.41(1H,d,J=8.8 Hz), 7.68(1H,s), 8.03-8.14(2H,m). MS (ESI) m/z:450(M+H)⁺.

Referential Example 224 (1R*,2S*,4R*)-N¹-[(5-Chloroindol-2-yl)carbonyl]-4-(1-hydroxy-1-methylethyl)-1,2-cyclohexanediaminehydrochloride

[0890]

[0891] A 4N hydrogen chloride solution in dioxane (10 ml) was added toan ethanol solution (5 ml) of(1R*,2S*,4R*)-N²tert-butoxycarbonyl-N¹-[(5-Chloroindol-2-yl)carbonyl]-4-(1-hydroxy-1-methylethyl)-1,2-cyclohexanediamine,and the mixture was stirred at room temperature for 12 hours. Thesolvent was distilled off under reduced pressure to obtain the titlecompound (100 mg) as a colorless oil.

[0892]¹H-NMR (DMSO-d⁶) δ: 1.07(3H,s), 1.08(3H,s), 1.10-2.08(7H,s),3.60-4.06(2H,m), 7.19(1H,dd,J=8.8 and 1.6 Hz), 7.27(1H,br.s),7.44(1H,d,J=8.8 Hz), 7.72(1H,br.s), 7.92(1H,br.s), 8.43(1H,d,J=6.8 Hz).MS (ESI) m/z: 350(M+H)⁺.

Referential Example 225(1R*,2S*,4S*)-1,2-Epoxy-4-methoxymethylcyclohexane

[0893]

[0894] 1) (1R*,3R*,4R*)-4-Iodo-6-oxabicyclo[3.2.1]octan-7-one (2.8 g)was dissolved in a mixed solvent of tetrahydrofuran (27 ml) and water (3ml), concentrated hydrochloric acid (0.1 ml) was added, and the mixturewas heated under reflux for 1 hour. The solvent was distilled off underreduced pressure to obtain(1R*,3R*,4R*)-3-hydroxy-4-iodocyclohexane-1-carboxylic acid (3.23 g) asa colorless solid.

[0895] 2) The product (3.22 g) obtained by the reaction described abovewas dissolved in tetrahydrofuran (50 ml), borane-dimethyl sulfidecomplex (2 M tetrahydrofuran solution, 47 ml) was added under icecooling, and the mixture was stirred at room temperature for 12 hours.The solvent was distilled off under reduced pressure, the residue wasdissolved in isopropanol (10 ml), a 1N aqueous solution (12 ml) ofsodium hydroxide was added, and the mixture was stirred for 12 hours.After the solvent was concentrated to about 1/5, the reaction mixturewas diluted with water and dichloromethane to stir it for 10 minutes. Anorganic layer was separated, successively washed with a saturatedaqueous solution of ammonium chloride and saturated saline and driedover anhydrous magnesium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by column chromatographyon silica gel (ethyl acetate:hexane=1:2) to obtain(1R*,2S*,4S*)-1,2-epoxy-4-hydroxymethylcyclohexane (1.25 g) as acolorless oil.

[0896] 3) The product (4.63 g) obtained by the reaction in 2) wasdissolved in tetrahydrofuran (50 ml), potassium bis(trimethylsilyl)amide(0.5N toluene solution, 80 ml) was added, and methyl iodide (2.93 ml)was then added. After heating the mixture to 0° C., it was stirred for 1hour, quenched with a saturated aqueous solution of ammonium chlorideand then diluted with diethyl ether. An organic layer was separated,washed with saturated saline and dried over anhydrous magnesium sulfate.The solvent was distilled off under reduced pressure, and the residuewas purified by column chromatography on silica gel (ethylacetate:hexane=1:4) to obtain the title compound (3.7 g) as a colorlessoil.

[0897]¹H-NMR (CDCl₃) δ: 0.89-1.63(5H,m), 1.80-2.05(2H,m),1.89-3.06(4H,m), 3.16(3H,s).

Referential Example 226(1R*,2R*,4S*)-2-Azido-4-methoxymethyl-1-cyclohexanol

[0898]

[0899] The title compound was obtained from(1R*,2S*,4S*)-1,2-epoxy-4-methoxymethylcyclohexane in a similar mannerto Referential Example 155.

[0900]¹H-NMR (CDCl₃) δ: 1.45-1.70(5H,m), 1.77-1.95(2H,m),1.98-2.08(1H,m), 3.30(2H,d,J=6.8 Hz), 3.35(3H,s), 3.45-3.65(2H,m).

Referential Example 227(1R*,2R*,4S*)-2-(tert-Butoxycarbonylamino)-4-methoxy-methyl-1-cyclohexanol

[0901]

[0902] The title compound was obtained from(1R*,2R*,4S*)-2-azido-4-methoxymethyl-1-cyclohexanol in a similar mannerto Referential Example 156.

[0903]¹H-NMR (CDCl₃) δ: 1.35-2.01(16H,m), 3.05(1H,br.s), 3.32(2H,d,J=7.1Hz), 3.34(3H,s), 3.44-3.62(2H,m), 4.59(1H,br.s).

Referential Example 228(1R*,2S*,4R*)-1-Azido-2-(tert-butoxycarbonylamino)-4-methoxymethylcyclohexane

[0904]

[0905] The title compound was obtained from(1R*,2R*,4S*)-2-(tert-butoxycarbonylamino)-4-methoxy-methyl-1-cyclohexanolin a similar manner to Referential Example 157.

[0906]¹H-NMR (CDCl₃) δ: 1.31-1.93(16H,m), 3.27(2H,d,J=6.4 Hz),3.32(3H,s), 3.57-3.70(1H,m), 3.67(1H,br.s), 3.95(1H,br.s).

Referential Example 229(1R*,2S*,4R*)-N²-(tert-Butoxycarbonyl)-4-methoxymethyl-1,2-cyclohexanediamine

[0907]

[0908] The title compound was obtained from(1R*,2S*,4R*)-1-azido-2-(tert-butoxycarbonylamino)-4-methoxymethylcyclohexanein a similar manner to Referential Example 47.

Referential Example 230 (1R*,2S*,4R*)-N²(tert-Butoxycarbonyl)-N¹-[(5-chloroindol-2-yl)carbonyl]-4-methoxymethyl-1,2-cyclohexanediamine

[0909]

[0910] The title compound was obtained from(1R*,2S*,4R*)-N²-(tert-butoxycarbonyl)-4-methoxymethyl-1,2-cyclohexanediamineand 5-chloroindole-2-carboxylic acid in a similar manner to ReferentialExample 159.

[0911]¹H-NMR (CDCl₃) δ: 1.12-2.31(16H,m), 3.14-3.30(2H,m), 3.34(3H,s),3.92(1H,br.s), 4.13(1H,br.s), 4.88(1H,br.s), 6.82(1H,s),7.21(1H,br.d,J=8.8 Hz), 7.33(1H,d,J=8.8 Hz), 7.60(1H,s), 8.09(1H,br.s),9.42(1H,br.s). MS (ESI) m/z: 436(M+H)⁺.

Referential Example 231 Mixture of(1R*,2S*,4R*,5S*)-N¹,N²-bis(benzyloxy-carbonyl)-4,5-dihydroxy-1,2-cyclohexanediamineand(1R*,2S*,4S*,5R*)-N¹,N²-bis(benzyloxycarbonyl)-4,5-dihydroxy-1,2-cyclohexanediamine

[0912]

[0913] The title compound was obtained fromcis-N¹,N²-bis(benzyloxycarbonyl)-4-cyclohexene-1,2-diamine in a similarmanner to Referential Example 183.

Referential Example 232 Mixture of(1R*,2S*,4R*,5S*)-N¹,N²-bis(benzyloxy-carbonyl)-4,5-isopropylidenedioxy-1,2-cyclohexanediamineand(1R*,2S*,4S*,5R*)-N¹,N²-bis(benzyloxycarbonyl)-4,5-isopropylidenedioxy-1,2-cyclohexanediamine

[0914]

[0915] The mixture (1.0 g) of(1R*,2S*,4R*,5S*)-N¹,N²-bis-(benzyloxycarbonyl)-4,5-dihydroxy-1,2-cyclohexanediamineand(1R*,2S*,4S*,5R*)-N¹,N²-bis(benzyloxycarbonyl)-4,5-dihydroxy-1,2-cyclohexanediaminewas dissolved in tetrahydrofuran (20 ml), and 2,2-dimethoxypropane (443ml) and pyridinium p-toluenesulfonate (61 mg) were added to stir themixture at room temperature for 2 hours. After 2,2-dimethoxypropane (2ml) was additionally added, and the mixture was stirred for 16 hours,saturated saline was added to the reaction mixture to extract it withethyl acetate. After the resultant organic layer was washed withsaturated saline and dried over anhydrous sodium sulfate, the solventwas distilled off under reduced pressure, and the residue was purifiedby column chromatography on silica gel (ethyl acetate:hexane=1:2-1:1) toobtain the title compound (1.10 g) as a colorless amorphous solid.

[0916]¹H-NMR (CDCl₃) δ: 1.50(3H,s), 1.54-1.64(2H,m), 1.66(3H,s),2.16-2.19(1H,m), 2.39(1H,br.d,J=14.2 Hz), 3.47-3.49(1H,m),3.80-3.82(1H,m), 4.16-4.19(1H,m), 4.25(1H,s), 4.95(1H,d,J=8.1 Hz),5.03(2H,d,J=12.0 Hz), 5.08(2H,d,J=12.0 Hz), 5.21(1H,d,J=8.1 Hz),7.31(10H,s).

Referential Example 233

[0917] Mixture of(1R*,2S*,4R*,5S*)-N¹-[(5-chloroindol-2-yl)-carbonyl]-4,5-isopropylidenedioxy-1,2-cyclohexanediamineand(1R*,2S*,4S*,5R*)-N¹-[(5-chloroindol-2-yl)-carbonyl]-4,5-isopropylidenedioxy-1,2-cyclohexanediamine

[0918] The title compound was obtained from the mixture of(1R*,2S*,4R*,5S*)-N¹,N²-bis(benzyloxycarbonyl)-4,5-isopropylidenedioxy-1,2-cyclohexanediamineand(1R*,2S*,4S*,5R*)-N¹,N²-bis(benzyloxycarbonyl)-4,5-isopropylidenedioxy-1,2-cyclohexanediaminein a similar manner to Referential Example 197.

[0919]¹H-NMR (DMSO-d₆) δ: 1.44(3H,s), 1.47(3H,s), 1.59-1.72(2H,m),1.93-1.96(1H,m), 2.23-2.26(2H,m), 2.66-2.69(1H,m), 2.93-2.95(1H,m),3.60-3.62(1H,m), 4.15-4.16(1H,m), 4.22(1H,s), 7.15(1H,s),7.17(1H,dd,J=8.5,2.0 Hz), 7.43(1H,d,J=8.5 Hz), 7.70(1H,s), 8.27(1H,s),11.76(1H,s).

Referential Example 234

[0920] Mixture of dimethyl(1R*,2S*,4R*,5S*)-4,5-dimethoxy-cyclohexane-1,2-dicarboxylate anddimethyl (1R*,2S*,4S*,5R*)-4,5-dimethoxycyclohexane-1,2-dicarboxylate

[0921] Under argon atmosphere, methyl iodide (2.00 ml) and sodiumhydride (60% oil suspension, 1.29 g) were successively added to atetrahydrofuran solution (25 ml) of a mixture (3.74 g) of(1R*,2S*,4R*,5S*)-4,5-dihydroxycyclohexane-1,2-dicarboxylic acid and(1R*,2S*,4S*,5R*)-4,5-dihydroxy-cyclohexane-1,2-dicarboxylic acid underice cooling, and the mixture was stirred overnight at room temperature.Diethyl ether and water was added to the reaction mixture to conductliquid separation. The resultant oil layer was dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure,and the residue was purified by column chromatography on silica gel(hexane:ethyl acetate=2:1) to obtain the title compound (2.64 g) as acolorless oil.

[0922]¹H-NMR (CDCl₃) δ: 1.35-1.45(1H,m), 1.80-1.90(1H,m),2.10-2.16(1H,m), 2.34-2.40(1H,m), 2.65-2.75(1H,m), 2.93-3.01(1H,m),3.20-3.26(1H,m), 3.35-3.45(7H,s), 3.69(6H,s). MS (ESI) m/z: 261(M+H)⁺.

Referential Example 235 Mixture of(1R*,2S*,4R*,5S*)-4,5-dimethoxycyclohexane-1,2-dicarboxydihydrazide and(1R*,2S*,4S*,5R*)-4,5-dimethoxycyclohexane-1,2-dicarboxydihydrazide

[0923]

[0924] Hydrazine monohydrate (1.97 ml) was added dropwise to an ethanolsolution (10 ml) of the mixture (2.64 g) of dimethyl(1R*,2S*,4R*,5S*)-4,5-dimethoxycyclohexane-1,2-dicarboxylate anddimethyl (1R*,2S*,4S*,5R*)-4,5-dimethoxycyclohexane-1,2-dicarboxylate,and the resultant mixture was heated overnight under reflux. After thereaction mixture was cooled to room temperature, it was concentrated,and diethyl ether was added to the residue to solidify the residue,thereby obtaining the title compound (1.07 g).

[0925]¹H-NMR (DMSO-d₆) δ: 1.25-1.35(1H,m), 1.55-1.70(2H,m),1.91-2.00(1H,m), 2.40-2.50(1H,m), 2.55-2.70(1H,m), 3.12-3.20(1H,m),3.20-3.40(6H,m), 3.64(1H,br.s), 4.06(4H,br.s), 8.85(1H,br.s),8.97(1H,br.s). MS (FAB) m/z: 261(M+H)⁺.

Referential Example 236 Mixture of(1R*,2S*,4R*,5S*)-4,5-dimethoxy-1,2-cyclohexanediamine hydrochloride and(1R*,2S*,4S*,5R*)-4,5-dimethoxy-1,2-cyclohexanediamine hydrochloride

[0926]

[0927] Ice (3.7 g), concentrated hydrochloric acid (1.9 ml) and diethylether (4.1 ml) were successively added to the mixture (1.07 g) of(1R*,2S*,4R*,5S*)-4,5-dimethoxy-cyclohexane-1,2-dicarboxydihydrazide and(1R*,2S*,4S*,5R*)-4,5-dimethoxycyclohexane-1,2-dicarboxydihydrazide.While stirring under ice cooling, water (1.6 ml) containing sodiumnitrite (709 mg) was added dropwise over 10 minutes. The mixture wasstirred for 5 minutes under ice cooling to separate a diethyl etherlayer, and the ether layer was dried over calcium chloride. Toluene (10ml) was added to the solution, only diethyl ether was carefullydistilled off under reduced pressure, and the resultant toluene solutionwas heated at 120° C. for 1 hour. The reaction mixture was addeddropwise to concentrated hydrochloric acid (3 ml) heated to 60° C., andthe mixture was stirred at 60° C. for 1 hour. After the reaction mixturewas cooled to room temperature, it was concentrated, and ethanol wasadded to the residue. The mixture was concentrated. Ethyl acetate wasadded, and powder deposited was collected by filtration to obtain thetitle compound (745 mg).

[0928]¹H-NMR (DMSO-d₆) δ: 1.50-1.60(1H,m), 1.75-1.87(1H,m),2.05-2.15(1H,m), 2.31-2.40(1H,m), 3.20-3.40(9H,m), 3.75(1H,br.s),8.67(6H,br.s). MS (FAB) m/z: 175(M+H)⁺.

Referential Example 237(1R*,2S*,4R*)-N²-(tert-Butoxycarbonyl)-N¹-[(5-chloroindol-2-yl)carbonyl]-4-hydroxymethyl-1,2-cyclohexanediamine

[0929]

[0930] The title compound was obtained from(1R*,2S*,4R*)-N²-(tert-butoxycarbonyl)-N¹-[(5-chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-1,2-cyclohexanediaminein a similar manner to Referential Example 221.

[0931]¹H-NMR (CDCl₃) δ: 0.78-2.30(16H,m), 3.41-3.59(3H,m),3.86-3.95(1H,m), 4.12-4.20(1H,m), 4.82-4.91(1H,m), 6.81(1H,s),7.17-7.40(2H,m), 7.60(1H,s), 8.03(1H,br.s), 9.18(1H,br.s). MS (ESI) m/z:422(M+H)⁺.

Referential Example 238(1R*,2S*,4R*)-4-Azidomethyl-N²-(tert-butoxycarbonyl)-N¹-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine

[0932]

[0933] The title compound was obtained from(1R*,2S*,4R*)-N²-(tert-butoxycarbonyl)-N¹-[(5-chloroindol-2-yl)carbonyl]-4-hydroxymethyl-1,2-cyclohexanediaminein a similar manner to Referential Example 127.

Referential Example 239(1R*,2S*)-N,N-Bis(tert-butoxycarbonyl)-4-[(1-ethoxycarbonyl)cyclopropan-1-yl]amino-1,2-cyclohexanediamine(Stereoisomer A and Stereoisomer B)

[0934]

[0935] Ethyl 1-aminocyclopropanecarboxylate hydrochloride (1.63 g) wasdissolved in dichloromethane (60 ml), and(1R*,2S*)-N,N-bis(tert-butoxycarbonyl)-4-oxo-1,2-cyclohexanediamine (3.0g) and sodium triacetoxyborohydride (2.51 g) were added to stir themixture at room temperature for 3 hours. An aqueous solution of sodiumhydrogencarbonate was added to separate an organic layer. The organiclayer was dried over anhydrous sodium sulfate. The solvent was distilledoff under reduced pressure, and the residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=3:1→1:1) to obtainthe title compounds (Stereoisomer A: 1.43 g and Stereoisomer B: 2.17 g)as colorless amorphous solids.

[0936] Stereoisomer A

[0937]¹H-NMR (CDCl₃) δ: 0.90-1.00(1H,m), 1.05-1.15(1H,m),1.20-1.85(29H,m), 2.00-2.10(1H,m), 3.20-3.35(2H,m), 3.65-3.75(1H,m),4.11(2H,q,J=7.1 Hz), 4.75-4.95(2H,m). MS (FAB) m/z: 442(M+H)⁺.

[0938] Stereoisomer B

[0939]¹H-NMR (CDCl₃) δ: 0.90-1.70(29H,m), 1.85-1.95(1H,m),1.95-2.10(1H,m), 2.20-2.30(1H,m), 2.85-2.95(1H,m), 3.20-3.45(2H,m),4.13(2H,q,J=7.1 Hz), 4.80-4.95(2H,m). MS (FAB) m/z: 442(M+H)⁺.

Referential Example 240(1R*,2S*)-N²-[(5-Chloroindol-2-yl)carbonyl]-4-[(1-ethoxycarbonyl)cyclopropan-1-yl]amino-1,2-cyclohexanediamine(Stereoisomer A) and(1R*,2S*)-N¹-[(5-chloroindol-2-yl)carbonyl]-4-[(1-ethoxycarbonyl)-cyclopropan-1-yl]amino-1,2-cyclohexanediamine(Stereoisomer A)

[0940](1R*,2S*)-N,N-Bis(tert-butoxycarbonyl)-4-[(1-ethoxycarbonyl)cyclopropan-1-yl]amino-1,2-cyclohexanediamine(Stereoisomer A) (1.34 g) was dissolved in dichloromethane (20 ml), asaturated ethanol solution (20 ml) of hydrochloric acid was added, andthe mixture was stirred for 90 minutes. The solvent was distilled offunder reduced pressure to obtain(1R*,2S*)-4-[(1-ethoxycarbonyl)cyclopropan-1-yl]amino-1,2-cyclohexanediaminehydrochloride (Stereoisomer A) (1.07 g) as a colorless solid.

[0941] The above-described product was treated in the same manner as inReferential Example 125 to obtain the title compound.

[0942] One Title Compound:

[0943]¹H-NMR (CDCl₃+CD₃OD) δ: 0.95-1.05(2H,m), 1.20-1.35(6H,m),1.45(1H,m), 1.50-1.90(4H,m), 2.00-2.10(1H,m), 3.05(1H,m), 3.30(1H,m),3.76(1H,m), 4.13(2H,q,J=7.1 Hz), 6.98(1H,d,J=2.2 Hz),7.21(1H,dd,J=8.8,2.2 Hz), 7.35(1H,d,J=8.8 Hz), 7.60(1H,d,J=1.5 Hz). MS(FAB) m/z: 419(M+H)⁺.

[0944] The Other Title Compound:

[0945]¹H-NMR (CDCl₃+CD₃OD) δ: 0.99(1H,m), 1.20-1.35(6H,m),1.35-1.90(6H,m), 2.15-2.25(1H,m), 2.61(1H,m), 3.36(1H,m),4.05-4.20(3H,m), 6.88(1H,s), 7.22(1H,dd, J=8.8,2.0 Hz), 7.35(1H,d,J=8.8Hz), 7.60(1H,d,J=2.0 Hz). MS (FAB) m/z: 419(M+H)⁺.

Referential Example 241 4-(tert-Butoxycarbonylamino)-1-cyclohexene

[0946]

[0947] 3-Cyclohexene-1-carboxylic acid (25.3 g) was dissolved intert-butanol (250 ml), triethylamine (28 ml) and diphenylphosphorylazide(43.0 ml) were added, and the mixture was stirred for 1 hour at roomtemperature and 2 days at 90° C. The solvent was distilled off underreduced pressure, and the residue was purified by column chromatographyon silica gel (dichloromethane) and then repurified by columnchromatography on silica gel (hexane:ethyl acetate=20:1) to obtain thetitle compound (24.9 g) as colorless crystals.

[0948]¹H-NMR (CDCl₃) δ: 1.45(9H,s), 1.45-1.60(1H,m), 1.80-1.90(2H,m),2.05-2.20(2H,m), 2.35-2.45(1H,m), 3.78(1H,br), 4.56(1H,br),5.55-5.65(1H,m), 5.65-5.75(1H,m).

Referential Example 242(1R*,2S*)-4-(tert-Butoxycarbonylamino)-1,2-dihydroxy-cyclohexane

[0949]

[0950] The title compound was obtained from4-(tert-butoxycarbonylamino)-1-cyclohexene in a similar manner toReferential Example 183.

[0951]¹H-NMR (CDCl₃) δ: 1.15-1.30(1/2H,m), 1.35-2.00(15H,m),2.15-2.30(3/2H,m), 2.40-2.60(1H,m), 3.64(1H,br), 3.75-3.90(3/2H,m),4.00(1/2H,br). MS (FAB) m/z: 232(M+H)⁺.

Referential Example 243(1R*,2S*)-4-(tert-Butoxycarbonylamino)-1,2-diazidocyclohexane(Stereoisomer A and Stereoisomer B)

[0952]

[0953] The respective title compounds were obtained from(1R*,2S*)-4-(tert-butoxycarbonylamino)-1,2-dihydroxycyclohexane in asimilar manner to Referential Example 127.

[0954] Stereoisomer A

[0955]¹H-NMR (CDCl₃) δ: 1.45(9H,s), 1.40-1.55(1H,m), 1.55-1.80(3H,m),1.95-2.15(2H,m), 3.53(1H,m), 3.59(1H,br), 3.80(1H,m), 4.70(1H,br).

[0956] Stereoisomer B

[0957]¹H-NMR (CDCl₃) δ: 1.27(1H,m), 1.44(9H,s), 1.40-1.55(1H,m),1.80-2.00(2H,m), 2.00-2.15(1H,m), 2.21(1H,m), 3.48(1H,m), 3.77(1H,br),3.89(1H,br), 4.34(1H,br).

Referential Example 244 4-(4-Pyridyl)benzoic acid hydrochloride

[0958]

[0959] 4-Bromopyridine hydrochloride (11.7 g) and 4-carboxyphenylboricacid (10.0 g) were dissolved in a mixed solvent of toluene (250 ml) andwater (250 ml), tetrakis(triphenylphosphine)palladium(0) (5.0 g) andanhydrous sodium carbonate (25.4 g) were successively added, and themixture was heated under reflux at 120° C. for 19 hours. After thereaction mixture was cooled to room temperature, ethyl acetate was addedto the reaction mixture to extract it with water. Concentratedhydrochloric acid was added to the water layer to acidify it. The waterlayer was washed with ethyl acetate and then concentrated, and solidsdeposited were collected to obtain the title compound (8.37 g) as acolorless solid.

[0960]¹H-NMR (DMSO-d₆) δ: 8.11(2H,d,J=8.8 Hz), 8.14(2H,d,J=8.8 Hz),8.35(2H,d,J=6.6 Hz), 8.97(2H,d,J=6.6 Hz). MS (FAB) m/z: 200(M+H)⁺.

Referential Example 245 Methyl 4-(4-pyridyl)benzoate

[0961]

[0962] 4-(4-Pyridyl)benzoic acid hydrochloride (12.4 g) was dissolved inmethanol (200 ml), concentrated sulfuric acid (5 ml) was added at roomtemperature, and the mixture was heated under reflux for 3 hours. Aftercompletion of the reaction, the solvent was distilled off, and asaturated aqueous solution of sodium hydrogencarbonate was added to theresidue to extract it with ethyl acetate. The extract was dried overanhydrous sodium sulfate, the solvent was distilled off, and hexane wasadded to the residue to solidify it, thereby obtaining the titlecompound (9.86 g) as colorless powder.

[0963]¹H-NMR (CDCl₃) δ: 3.96(3H,s), 7.54(2H,d,J=5.9 Hz), 7.71(2H,dJ=8.3Hz), 8.16(2H,d,J=8.3 Hz), 8.71(2H,d,J=5.9 Hz).

Referential Example 246 4-(4-Methoxycarbonylphenyl)pyridine N-oxide

[0964]

[0965] Methyl 4-(4-pyridyl)benzoate (1.49 g) was dissolved indichloromethane (30 ml), 70% m-chloroperbenzoic acid (3.46 g) was added,and the mixture was stirred at room temperature for 1 hour. An aqueoussolution of sodium sulfite was added to conduct liquid separation. Theresultant organic layer was washed with a saturated aqueous solution ofsodium hydrogencarbonate and then dried over anhydrous sodium sulfate.The solvent was distilled off to obtain the title compound (1.33 g) aswhite powder.

[0966]¹H-NMR (DMSO) δ: 3.88(3H,s), 7.86(2H,d,J=7.2 Hz), 7.94(2H,d,J=8.3Hz), 8.05(2H,d,J=8.3 Hz), 8.30(2H,d,J=7.2 Hz). MS (FAB) m/z: 230(M+H)⁺.

Referential Example 247 4-(4-Carboxyphenyl)pyridine N-oxide

[0967]

[0968] 4-(4-Carboxyphenyl)pyridine N-oxide (802 mg) was dissolved indioxane (20 ml), a 1N aqueous solution (5 ml) of sodium hydroxide wasadded, and the mixture was refluxed for 1 hour and then stirred at roomtemperature for 2 hours. 1N Hydrochloric acid (5 ml) was added toneutralize it. Further, water (5 ml) was added, and precipitate formedwas collected by filtration to obtain the title compound (627 mg) as awhite solid.

[0969]¹H-NMR (DMSO) δ: 7.85(2H,d,J=7.2 Hz), 7.91(2H,d,J=8.3 Hz),8.03(2H,d,J=8.3 Hz), 8.30(2H,d,J=7.2 Hz).

Referential Example 248 2-(4-Carboxyphenyl)pyridine N-oxide

[0970]

[0971] 2-(4-Ethoxycarbonylphenyl)pyridine N-oxide (260 mg) synthesizedfrom 4-(2-pyridyl)benzoic acid in the same manner as in the aboveReferetnial Example was dissolved in 1,4-dioxane (10 ml), a 1N aqueoussolution (2.00 ml) of sodium hydroxide was added, and the mixture washeated under reflux for 2 hours. The reaction mixture was concentratedunder reduced pressure, 1N hydrochloric acid (6 ml) was added to theresidue, and precipitate formed was collected by filtration to obtainthe title compound (202 mg) as a colorless amorphous solid.

[0972]¹H-NMR (DMSO-d₆) δ: 7.41-7.45(2H,m), 7.65-7.69(1H,m),7.94(2H,d,J=8.3 Hz), 8.02(2H,d,J=8.3 Hz), 8.34-8.38(1H,m), 13.09(1H,s).MS (FAB) m/z: 216(M+H)⁺.

Referential Example 249(1R,2R,4S)-N²-(tert-Butoxycarbonyl)-N¹-(5-chloroindol-2-yl)carbonyl-4-ethoxycarbonyl-1,2-cyclohexanediamine

[0973]

[0974] 1)(1R,2R,4S)-N²-tert-Butoxycarbonyl-4-ethoxycarbonyl-1,2-cyclohexanediaminewas obtained as a pale brown oil from ethyl(1S,3R,4R)-4-azido-3-(tert-butoxycarbonylamino)cyclohexane-1-carboxylatein a similar manner to Referential Example 158.

[0975] 2) The title compound was obtained as a colorless solid from theproduct described above in a similar manner to Referential Example 159.

[0976]¹H-NMR (CDCl₃) δ: 1.22-1.72(5H,m), 2.15-2.28(2H,m),2.41-2.49(1H,m), 2.85(1H,brs), 3.62-3.75(1H,m), 3.78-3.92(1H,m),4.12-4.28(2H,m), 4.56-4.63(1H,m), 6.88(1H,brs), 7.20(1H,dd,J=8.8and2.0Hz), 7.33(1H,d,J=8.8 Hz), 7.52-7.57(1H,m), 7.59(1H,d,J=2.0 Hz),9.24(1H,s). MS (ESI) m/z: 464(M+H)⁺.

Referential Example 250 6-Chloro-2-cyanoquinoline

[0977]

[0978] 6-Chloroquinoline (2.50 g) was dissolved in dichloromethane (25ml), and m-chloroperbenzoic acid (3.71 g) was added under ice cooling tostir the mixture at room temperature for 1 hour. After the reactionmixture was diluted with dichloromethane, the diluted mixture was washedwith an aqueous solution of sodium thiosulfate and an aqueous solutionof sodium hydroxide and dried over anhydrous sodium sulfate. The solventwas distilled off under reduced pressure, and the residue was dissolvedin dichloromethane (40 ml), and trimethylsilyl cyanide (2.0 ml) andN,N-dimethylcarbamoyl chloride (1.50 ml) were added to heat theresultant mixture for 9 hours under reflux. After trimethylsilyl cyanide(2.0 ml) and N,N-dimethylcarbamoyl chloride (1.50 ml) were additionallyadded, and the mixture was heated for 16 hours under reflux, thereaction mixture was diluted with dichloromethane, and a 10% aqueoussolution (40 ml) of potassium carbonate was added to stir the mixturefor 30 minutes. After an organic layer was separated and dried overanhydrous sodium sulfate, the solvent was distilled off under reducedpressure. Dichloromethane was added to the residue, and crystalsdeposited were collected by filtration to obtain the title compound(1.77 g) as colorless crystals. Further, a mother liquor was purified bycolumn chromatography on silica gel (dichloromethane) to obtain thetitle compound (0.80 g) as pale yellow crystals.

[0979]¹H-NMR (DMSO-d₆) δ: 7.94(1H,dd,J=9.0,2.2 Hz), 8.09(1H,d,J=8.5 Hz),8.15(1H,d,J=9.0 Hz), 8.29(1H,d,J=2.2 Hz), 8.63(1H,d,J=8.5 Hz). MS (FAB)m/z: 189(M+H)⁺.

Referential Example 251 6-Chloroquinoline-2-carboxylic acid

[0980]

[0981] 6-Chloro-2-cyanoquinoline (1.73 g) was dissolved in concentratedhydrochloric acid (40 ml), and the solution was heated for 19 hoursunder reflux. The reaction mixture was cooled to room temperature, anddeposits were collected by filtration and then washed with water toobtain the title compound (1.81 g) as a colorless solid.

[0982]¹H-NMR (DMSO-d₆) δ: 7.87(1H,dd,J=9.0,2.4 Hz), 8.10-8.20(2H,m),8.24(1H,d,J=2.2 Hz), 8.52(1H,d,J=8.5 Hz). MS (FAB) m/z:208(M+H)⁺.

Referential Example 252(1S,2R,4S)-N¹-Benzyloxycarbonyl-N²-(tert-butoxycarbonyl)-4-ethoxycarbonylcyclohexanediamine

[0983]

[0984](1S,2R,4S)-N²-(tert-Butoxycarbonyl)-4-ethoxy-carbonylcyclohexanediamine(3.10 g) was dissolved in tetrahydrofuran (50 ml), and a saturatedaqueous solution (50 ml) of sodium hydrogencarbonate waa added. Afterbenzyloxycarbonyl chloride (1.71 ml) was added dropwise to the reactionmixture under ice cooling, the mixture was stirred at room temperaturefor 3 days. Ethyl acetate (200 ml) and water (200 ml) were added to thereaction mixture to conduct liquid separation. After the resultantorganic layer was dried over anhydrous sodium sulfate, the solvent wasdistilled off under reduced pressure. Solids deposited were collected byfiltration to obtain the title compound (3.24 g) as a colorless solid.

[0985]¹H-NMR (CDCl₃) δ: 1.24 (3H,t,J=7.1 Hz), 1.29-1.44 (1H,m),1.51-1.64(1H,m), 1.72-2.02(4H,m), 2.27-2.40(1H,m), 3.60-3.73(1H, m),4.00-4.15(3H, m), 4.59(1H,br.s), 5.01-5.13(2H,m), 5.26(1H, br.s),7.27-7.38(5H, m).

Referential Example 253 (1S,2R,4S)-4-Carboxy-N¹-benzyloxycarbonyl-N²-(tert-butoxycarbonyl)-1,2-cyclohexanediamine

[0986]

[0987](1S,2R,4S)-N¹-Benzyloxycarbonyl-N²-(tert-butoxy-carbonyl)-4-ethoxycarbonyl-1,2-cyclohexanediamine(620 mg) was dissolved in tetrahydrofuran (10 ml), and an aqueoussolution (5.0 ml) of lithium hydroxide monohydrate (93 mg) was added tostir the mixture at room temperature for 16 hours. After lithiumhydroxide monohydrate (221 mg) was additionally added to the reactionmixture, and the mixture was stirred at room temperature for 2 hours,the reaction mixture was neutralized with 1N hydrochloric acid andextracted with methylene chloride. An organic layer was washed withsaturated saline and then dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure to obtain the titlecompound (580 mg) as a colorless foamy substance.

[0988]¹H-NMR (CDCl₃) δ: 1.22-2.02(6H, m), 1.44(9H,s), 2.27-2.45(1H,br),3.71-3.76(1H,br), 4.09(1H,br),4.66-4.71(1H,br), 5.10(2H,s), 5.26(1H,br),6.15(1H,br), 7.35(5H,s). MS (FAB m/z: 393(M+H)⁺.

Referential Example 254(1S,2R,4S)-N¹-Benzyloxycarbonyl-N²-(tert-butoxycarbonyl)-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamine

[0989]

[0990](1S,2R,4S)-4-Carboxy-N¹-benzyloxycarbonyl-N²-(tert-butoxycarbonyl)-1,2-cyclohexanediaminewas dissolved in dichloromethane (50 ml), and dimethylaminehydrochloride (240 mg), triethylamine (0.41 ml),3-(3-dimethylamino-propyl)-1-ethylcarbodiimide hydrochloride (420 mg)and 1-hydroxybenzotriazole monohydrate (340 mg) were added to stir themixture at room temperature for 1 hour. Dimethylamine hydrochloride (480mg) and triethylamine (0.82 ml) were additionally added to the reactionmixture to stir the mixture at room temperature for additional 18 hours.The reaction mixture was poured into water to separate an organic layer.After the organic layer was washed with 1N hydrochloric acid andsaturated saline and dried over anhydrous sodium sulfate. The solventwas distilled off under reduced pressure, and the residue was purifiedby column chromatography on silica gel (methanol:methylenechloride=3:47→2:23) to obtain the title compound (620 mg) as a colorlessfoamy substance.

[0991]¹H-NMR (CDCl₃) δ: 1.26-1.98 (6H,m), 1.44 (9H,s), 2.57-2.63(1H,m),2.93(3H,s), 3.02(3H,s), 3.70(1H,br.s), 4.14 (1H,br.s), 4.65(1H,br.s),5.10(2H,s), 5.05-5.13(1H,br), 7.35(5H,s). MS (FAB) m/z=420(M+H)⁺.

Referential Example 255(1S,2R,4S)-N²-(tert-Butoxycarbonyl)-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamine

[0992]

[0993](1S,2S,4R)-N¹-Benzyloxycarbonyl-N²-(tert-butoxycarbonyl)-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamine(560 mg) was dissolved in tetrahydrofuran (100 ml), and 10% palladium oncarbon (220 mg) was added to stir the mixture for 17 hours in a hydrogenatmosphere. After the catalyst was removed by filtration, the filtratewas concentrated to obtain the title compound (370 mg) as a colorlessoil.

[0994]¹H-NMR (CDCl₃) δ: 1.21-1.87(6H,m), 1.45(9H,s), 2.64-2.75(1H,m),2.92(3H,s), 3.02(3H,s), 3.73-3.78(2H,br.s), 4.93(1H,br.s). MS (FAB) m/z:286(M+H)⁺.

Referential Example 256(1S,2R,4S)-N²-(tert-Butoxycarbonyl)-N¹-[(6-chloro-quinolin-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamine

[0995]

[0996] The title compound was obtained from(1S,2R,4S)-N²-(tert-butoxycarbonyl)-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamineand 6-chloroquinoline-2-carboxylic acid in a similar manner toReferential Example 159.

[0997]¹H-NMR (CDCl₃) δ: 1.41(9H,br), 1.50-1.70(1H,m), 1.75-1.95(2H,m),1.95-2.25(3H,m), 2.65-2.80(1H,m), 2.96(3H,s), 3.07(3H,s),4.15-4.30(1H,m), 4.30-4.40(1H,m), 4.95(1H,br), 7.66(1H,d,J=8.8 Hz),7.84(1H,s), 8.00(1H,d,J=8.8 Hz), 8.19(1H,d,J=8.6 Hz), 8.30(1H,d,J=8.6Hz) MS (FAB) m/z: 475(M+H)⁺.

Referential Example 257 (±)-N-Formyl-(4-chlorophenyl)alanine methylester

[0998]

[0999] (±)-(4-Chlorophenyl)alanine methyl ester hydrochloride (2.00 g)was suspended in dichloromethane (20 ml), and3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (1.60 g),1-hydroxybenzotriazole monohydrate (1.23 g), N-methylmorpholine (1.90ml) and formic acid (0.30 ml) were added to stir the mixture for 15minutes. After a process in which formic acid (0.30 ml) was additionallyadded to stir the mixture for 15 minutes was repeated 3 times, thereaction mixture was diluted with dichloromethane. After an ograniclayer was washed with water and then dried over anhydrous sodiumsulfate, the solvent was distilled off under reduced pressure. Theresidue was purified by column chromatography on silica gel(dichloromethane methanol=40:1) to obtain the title compound (1.21 g) asa yellow oil.

[1000]¹H-NMR (CDCl₃) δ: 3.10(1H,dd,J=13.9,5.6 Hz), 3.18(1H,dd,J=13.9,5.9Hz), 3.75(3H,s), 4.95(1H,m), 6.07(1H,br), 7.05(2H,d,J=8.3 Hz),7.27(2H,d,J=8.3 Hz), 8.18(1H,s). MS (FAB) m/z: 242(M+H)⁺.

Referential Example 258 Methyl 7-chloroisoquinoline-3-carboxylate

[1001]

[1002] (±)-N-Formyl-(4-chlorophenyl)alanine methyl ester (1.45 g) wasdissolved in dichloromethane (40 ml), and oxalyl chloride (0.57 ml) wasadded dropwise. After the mixture was stirred at room temperature for 30minutes, ferric chloride (1.17 g) was added at an ambient temperature ofabout −10° C. to stir the mixture at room temperature for 4 days. 1NHydrochloric acid was added, and the resultant mixture was diluted withdichloromethane to separate an organic layer. The organic layer wasdried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was dissolved in methanol (38 ml), andconcentrated sulfuric acid (2 ml) was added to heat the mixture for 20hours under reflux. An aqueous solution of sodium hydrogencarbonate wasadded to the reaction mixture, the resultant mixture was extracted withdichloromethane, and the extract was dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, and theresidue was purified by column chromatography on silica gel(hexane:ethyl acetate=2:1→ethyl acetate) to obtain the title compound(0.25 g) as colorless crystals.

[1003]¹H-NMR (CDCl₃) δ: 4.07(3H,s), 7.74(1H,dd,J=8.8,2.0 Hz),7.94(1H,d,J=8.8 Hz), 8.06(1H,d,J=2.0 Hz), 8.59(1H,s), 9.28(1H,s).

Referential Example 259 7-Chloroisoquinoline-3-carboxylic acidhydrochloride

[1004]

[1005] Methyl 7-chloroisoquinoline-3-carboxylate (0.23 g) was dissolvedin concentrated hydrochloric acid (10 ml) to heat the mixture for 18hours under reflux. The temperature of the reaction mixture was droppedto room temperature, and deposits were collected by filtration and thenwashed with water to obtain the title compound (0.21 g) as a colorlesssolic.

[1006]¹H-NMR (DMSO-d₆) δ: 7.96(1H,m), 8.29(1H,d,J=8.5 Hz), 8.44(1H,s),8.72(1H,s), 9.45(1H,d,J=6.6 Hz). MS (FAB) m/z: 208(M+H)⁺.

Referential Example 260 (1S,2R, 4S)-N²-(tert-Butoxycarbonyl)-N¹-[(7-chloroisoquinolin-3-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamine

[1007]

[1008] The title compound was obtained from(1S,2R,4S)-N²-(tert-butoxycarbonyl)-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamineand 7-chloroisoquinoline-2-carboxylic hydrochloride in a similar mannerto Referential Example 159.

[1009]¹H-NMR (CDCl₃) δ: 1.30-1.65(10H,br), 1.75-1.90(2H,m),1.90-2.25(3H,m), 2.65-2.90(1H,br), 2.96(3H,s), 3.08(3H,s),4.20-4.30(1H,m), 4.30-4.40(1H,m), 4.93(1H,br), 7.68(1H,m), 7.90(1H,br),7.99(1H,s), 8.35-8.70(2H,m), 9.01(1H,br). MS (FAB) m/z: 475(M+H)⁺.

Example 1(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopropanediaminehydrochloride

[1010]

[1011] 1-Hydroxybenzotriazole monohydrate (71 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100 mg)were added to a solution with(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclopropanediamine (108mg) and lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate (124mg) dissolved in N,N-dimethylformamide (3 ml) at room temperature, andthe mixture was stirred for 8 days. After concentrating the reactionmixture under reduced pressure using a vacuum pump, water (50 ml) and asaturated aqueous solution (50 ml) of sodium hydrogencarbonate wereadded to the residue to conduct extraction with dichloromethane. Theresultant organic layers were collected and dried over anhydrous sodiumsulfate, the solvent was distilled off under reduced pressure, and theresidue was purified by preparative thin-layer chromatography on silicagel (dichloromethane:methanol=10:1). After 1N hydrochloric acid,dichloromethane and methanol were added to the thus-obtained amorphoussubstance, the mixture was concentrated to obtain the title compound (72mg) as a colorless solid.

[1012]¹H-NMR (DMSO-d₆) δ: 1.15-1.35(2H,m), 2.88(3H,s), 2.95-3.25(4H,m),3.35-3.75(2H,m), 4.32-4.45(1H,m), 4.68(1H,br,J=15.4 Hz), 7.08(1H,s),7.17(1H,dd,J=8.6,2.1 Hz), 7.41(1H,d,J=8.6 Hz), 7.70(1H,s),8.50(1H,br,J=11.0 Hz), 8.56(1H,br.s), 11.56(1H,br,J=19.3 Hz),11.86(1H,s). MS (FAB) m/z: 430(M+H)⁺.

Example 2(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclobutanediaminehydrochloride

[1013]

[1014] Lithium5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxylate (136mg), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (255mg) and 1-hydroxybenzotriazole monohydrate (90 mg) were added to asolution with(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclobutanediamine (117 mg)dissolved in N,N-dimethylformamide (5 ml), and the mixture was stirredovernight at room temperature. The solvent was then distilled off underreduced pressure using a vacuum pump, and dichloromethane and asaturated aqueous solution of sodium hydrogencarbonate were added to theresidue to conduct liquid separation. The resultant organic layer waswashed with saturated saline and dried over anhydrous sodium sulfate,the solvent was distilled off under reduced pressure, and the residuewas purified by flash column chromatography on silica gel(methanol:dichloromethane=7:93). After ethyl acetate and a 1N ethanolsolution of hydrochloric acid were added to the thus-obtained compoundto acidify it, and the solvent was distilled off under reduced pressure.Ethyl acetate was added again, and precipitate formed was collected byfiltration and dried to obtain the title compound (56 mg) as a colorlesspowder.

[1015]¹H-NMR (DMSO-d₆) δ: 2.00-2.35(4H,m), 2.88(3H,m), 3.10(2H,br.s),3.20-3.75(3H,m), 4.20-4.85(3H,m), 7.09(1H,s), 7.16(1H,d,J=8.8 Hz),7.38(1H,d,J=8.8 Hz), 7.71(1H,s), 8.63(1H,d,J=8.3 Hz), 8.85(1H,d,J=8.6Hz), 10.85-11.20(1H,br), 11.81(1H,s). MS (FAB) m/z: 444(M+H)⁺.

Example 3(±)-trans-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride

[1016]

[1017] 5-Chloroindole-2-carboxylic acid (80 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (98 mg),1-hydroxybenzotriazole monohydrate (23 mg) and triethylamine (141 μl)were added to a solution with(±)-trans-N-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride (120 mg) dissolved in N,N-dimethylformamide (5 ml), andthe mixture was stirred at room temperature for 3 days. The solvent wasdistilled off under reduced pressure, and dichloromethane and asaturated aqueous solution of sodium hydrogencarbonate were added to theresidue to conduct liquid separation. The resultant organic layer wasdried over anhydrous sodium sulfate, the solvent was distilled off underreduced pressure, and the residue was purified by flash columnchromatography on silica gel (dichloromethane:methanol=93:7). Afterdichloromethane (5 ml) and a 1N ethanol solution (282 μl) ofhydrochloric acid were added to the thus-obtained pale yellow solid.Ethyl acetate was added, solvent was distilled off under reducedpressure and precipitate formed was collected by filtration to obtainthe title compound (109 mg) as a pale yellow solid.

[1018]¹H-NMR (DMSO-d₆) δ: 1.64-1.74(4H,m), 1.98-2.02(2H,m), 2.89(3H,s),3.14(2H,br.s), 3.47-3.65(2H,m), 4.29-4.63(4H,m), 7.10(1H,d,J=1.5 Hz),7.14(1H,dd,J=8.5,2.0 Hz), 7.38(1H,d,J=8.5 Hz), 7.68(1H,d,J=2.0 Hz),8.55(1H,d,J=8.5 Hz), 8.91(1H,d,J=8.5 Hz), 11.49(1H,br.s), 11.76(1H,s).MS (ESI) m/z: 458(M+H)⁺.

Example 4(±)-cis-N¹-[(5-Chloroindol-2-yl)sulfonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride

[1019]

[1020] The title compound (182 mg) was obtained as a pale yellow solidby dissolving(±)-cis-N-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-1,2-cyclopentane-diamine(409 mg), lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate (250mg) and 1-hydroxybenzotriazole monohydrate (61 mg) inN,N-dimethyl-formamide (7 ml) and causing1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (259 mg) toreact as a condensing agent in a similar manner to Example 2.

[1021]¹H-NMR (DMSO-d₆) δ: 1.43-1.85(6H,m), 2.94(3H,s), 3.15(2H,br.s),3.49-3.84(3H,m), 4.23(1H,t,J=7.5 Hz), 4.35-4.63(2H,brm), 6.78(1H,s),7.22(1H,dd,J=8.8,2.0 Hz), 7.30(1H,br.s), 7.54(1H,br.s),7.88,7.90(1H,each s), 8.15(1H,br,J=8.3 Hz), 11.55-11.75(1H,brm),12.01(1H,br.s). MS (ESI) m/z: 494(M+H)⁺.

Example 5 (±) -cis-N¹-[(5-Chloroindol-2-yl)sulfonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1022]

[1023](±)-cis-N-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminetrifluoroacetate (400 mg) was suspended in dichloromethane (10 ml),triethylamine (0.514 ml) and 5-chloro-1-phenylsulfonylindole-2-sulfonylchloride (Japanese Patent Application Laid-Open No. 2000-119253) (319mg) were added, and the mixture was stirred at room temperature for 15minutes. After water was added to the reaction mixture to conduct liquidseparation, the resultant organic layer was dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, and theresidue was purified by column chromatography on silica gel(dichloromethane:methanol=100:3) to obtain a pale yellow foamysubstance. This substance was dissolved in tetrahydrofuran (3 ml), andmethanol (2 ml) and a 1N aqueous solution (1.5 ml) of sodium hydroxidewere added to heat the mixture under reflux for 2 hours. The reactionmixture was concentrated under reduced pressure, and dichloromethane and1N hydrochloric acid were added to the residue to conduct liquidseparation. After the resultant organic layer was dried over anhydroussodium sulfate, the solvent was distilled off under reduced pressure,and the residue was purified by column chromatography on silica gel(dichloromethane:methanol=100:3) to obtain a pale yellow foamysubstance. This substance was added to 1N hydrochloric acid (1 ml), andthe mixture was concentrated under reduced pressure to obtain the titlecompound (108 mg) as a pale yellow foamy substance.

[1024]¹H-NMR (DMSO-d₆) δ: 1.20-1.78(8H,m), 2.94(3H,s), 3.13(2H,br.s),3.22-3.40(1H,m), 3.44-3.70(3H,m), 3.83-3.95(1H,m), 4.20-4.70(1H,m),6.78(1H,s), 7.18-7.30(2H,m), 7.44(1H,s), 7.69(1H,br.s), 8.09(1H,br.s),11.92(1H,s). MS (FAB) m/z: 508(M+H)⁺.

Example 6(±)-trans-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1025]

[1026] 5-Chloroindole-2-carboxylic acid (109 mg), 1-hydroxybenzotriazolemonohydrate (9 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (321 mg) and triethylamine (0.232 ml) were added to asolution with(±)-trans-N-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminetrifluoroacetate (300 mg) dissolved in N,N-dimethylformamide (20 ml),and the mixture was stirred overnight at room temperature. The reactionmixture was concentrated under reduced pressure using a vacuum pump, anddichloromethane and water were added to the residue to conduct liquidseparation. The resultant organic layer was dried over anhydrous sodiumsulfate, the solvent was distilled off under reduced pressure, and theresidue was purified by column chromatography on silica gel(dichloromethane:methanol=25:1) to obtain a colorless foamy substance.1N hydrochloric acid (1 ml) was added to this substance and the solventwas distilled off under reduced pressure to obtain the title compound(203 mg) as a pale brown foamy substance.

[1027]¹H-NMR (DMSO-d₆) δ: 1.25-1.40(2H,m), 1.46-1.81(4H,m),1.88-1.98(2H,m), 2.89(3H,s), 3.00-3.76(5H,m), 3.86-3.97(1H,m),4.00-4.10(1H,m), 4.25-4.72(1H,m), 7.03(1H,s), 7.12(1H,dd,J=8.5,1.2 Hz),7.38(1H,d,J=8.5 Hz), 7.64(1H,s), 8.28(1H,d,J=8.5 Hz), 8.54(1H,d,J=8.5Hz), 11.70(1H,s) MS (FAB) m/z: 472(M+H)⁺.

Example 7(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1028]

[1029] The title compound was obtained from(±)-cis-N-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminetrifluoroacetate in a similar manner to Example 6.

[1030]¹H-NMR (DMSO-d₆) δ: 1.35-1.70(6H,m), 1.80-2.06(2H,m), 2.89(3H,s),3.00-3.27(2H,m), 3.35-3.51(1H,m), 3.57-3.82(1H,m), 4.15-4.30(2H,m),4.32-4.48(1H,m), 4.60-4.74(1H,m), 7.15(1H,s), 7.17(1H,dd,J=8.8,2.0 Hz),7.41(1H,d,J=8.6 Hz), 7.70(1H,d,J=2.0 Hz), 8.14(1H,br.s),8.36-8.48(1H,m), 11.51(1H,br.s), 11.86(1H,s). MS (FAB) m/z: 472(M+H)⁺.

Example 8(1S,2R)-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[1031]

[1032] The title compound was obtained from(1R,2S)-N¹-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(Isomer B) in a similar manner to Example 6.

[1033] [α]_(D)−128.7° (20.8° C., C=0.5, CHCl₃). ¹H-NMR (DMSO-d₆) δ:1.38-1.52(2H,m), 1.55-1.70(4H,m), 1.89-2.07(2H,m), 2.38(3H,s),2.70-2.77(2H,m), 2.78-2.87(2H,m), 3.63(2H,s), 4.20-4.30(2H,m),7.12(1H,s), 7.14(1H,d,J=8.8 Hz), 7.41(1H,d,J=8.8 Hz), 7.67(1H,s),8.10(1H,d,J=6.9 Hz), 8.30(1H,d,J=8.1 Hz), 11.77(1H,s). MS (FAB) m/z:472(M+H)⁺.

Example 9(1R,2S)-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-carbonyl]-1,2-cyclohexanediamine

[1034]

[1035] The title compound was obtained from(1S,2R)-N¹-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(Isomer A) in a similar manner to Example 6.

[1036] [α]_(D) +125.7 ° (20.8° C., C=0.5, CHCl₃). ¹H-NMR (DMSO-d₆) δ:1.38-1.52(2H,m), 1.55-1.70(4H,m), 1.89-2.07(2H,m), 2.37(3H,s),2.70-2.76(2H,m), 2.78-2.86(2H,m), 3.63(2H,s), 4.20-4.30(2H,m),7.13(1H,s), 7.15(1H,d,J=8.8 Hz), 7.41(1H,d,J=8.8 Hz), 7.67(1H,s),8.10(1H,d,J=6.9 Hz), 8.30(1H,d,J=8.1 Hz), 11.78(1H,s). MS (FAB) m/z:472(M+H)⁺.

Example 10(±)-cis-N¹-[(6-Chloronaphthalen-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-carbonyl]-1,2-cyclohexanediaminehydrochloride

[1037]

[1038] The title compound (186 mg) was obtained as a pale brown foamysubstance by dissolving(±)-cis-N-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride (275 mg), 6-chloronaphthalene-2-carboxylic acid (Eur. J.Chem. -Chim. Ther., 1984, Vol. 19, pp. 205-214) (148 mg), triethylamine(0.298 ml) and 1-hydroxybenzotriazole monohydrate (11 mg) inN,N-dimethylformamide (20 ml) and causing1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (412 mg) toreact as a condensing agent in a similar manner to Example 6.

[1039]¹H-NMR (DMSO-d₆) δ: 1.40-1.56(2H,m), 1.57-1.77(4H,m),1.90-2.10(2H,m), 2.90(3H,s), 3.13(2H,br.s), 3.28-3.74(2H,m),4.26(2H,br.s), 4.30-4.74(2H,m), 7.59(1H,d,J=8.6 Hz), 7.90(1H,d,J=8.6Hz), 7.98(1H,d,J=8.3 Hz), 8.03-8.11(2H,m), 8.25-8.58(3H,m),11.52(1H,br.s). MS (FAB) m/z: 483(M+H)⁺.

Example 11(±)-trans-N¹-[(6-Chlorobenzo[b]thiophen-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1040]

[1041] The title compound (239 mg) was obtained as a pale brown foamysubstance by dissolving(±)-trans-N-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride (255 mg, 0.665 mmol),6-chlorobenzo[b]thiophene-2-carboxylic acid (Japanese Patent ApplicationLaid-Open No. 2000-119253) (141 mg), triethylamine (0.276 ml) and1-hydroxybenzotriazole monohydrate (10 mg) in N,N-dimethylformamide (20ml) and causing 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (382 mg) to react as a condensing agent in a similarmanner to Example 6.

[1042]¹H-NMR (DMSO-d₆) δ: 1.20-1.98(8H,m), 2.88(3H,s), 3.00-3.72(4H,m),3.84-4.09(2H,m), 4.20-4.75(2H,m), 7.41(1H,dd,J=8.6,1.7 Hz),7.91(1H,d,J=8.6 Hz), 7.99(1H,s), 8.12(1H,s), 8.54-8.67(2H,m),11.53(1H,br.s). MS (FAB) m/z: 489(M+H)⁺.

Example 12(±)-trans-N¹-[(5-Fluoroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1043]

[1044] The title compound was obtained from(±)-trans-N-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and 5-fluoroindole-2-carboxylic acid in a similar mannerto Example 6.

[1045]¹H-NMR (DMSO-d₆) δ: 1.20-1.38(2H,m)., 1.40-1.57(1H,m),1.54-1.68(1H,m), 1.71(2H,d,J=7.3 Hz), 1.88(2H,d,J=12.0 Hz), 2.86(3H,s),2.95-3.24(2H,m), 3.40(1H,br.s), 3.63(1H,br.s), 3.90(1H,br.s),3.97-4.10(1H,m), 4.20-4.44(1H,m), 4.53-4.70(1H,m), 6.98(1H,dd,J=9.2,2.3Hz), 7.01(1H,s), 7.31-7.39(2H,m), 8.26(1H,d,J=8.6 Hz), 8.59(1H,d,J=8.4Hz), 11.21(1/2H,br.s), 11.42(1/2H,br.s), 11.60(1H,s). MS (ESI) m/z:456(M+H)⁺.

Example 13(±)-cis-N¹-[(5-Fluoroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1046]

[1047] The title compound was obtained from(±)-cis-N-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and 5-fluoroindole-2-carboxylic acid in a similar mannerto Example 6.

[1048]¹H-NMR (DMSO-d₆) δ: 1.43(2H,br.s), 1.61(4H,br.s), 1.82-2.08(2H,m),2.89(3H,s), 3.00-3.23(2H,m), 3.44(1H,br.s), 3.65(1H,br.s),4.23(1H,d,J=16.2 Hz), 4.26(1H,br.s), 4.41(1H,br.s), 4.68(1H,d,J=16.2Hz), 6.98-7.07(1H,m), 7.14(1H,s), 7.37-7.43(2H,m), 8.01(1H,br.s),8.35-8.52(1H,br), 11.37(1H,br.s), 11.74(1H,s). MS (ESI) m/z: 456(M+H)⁺.

Example 14(±)-trans-N¹-[(5-Chloro-6-fluoroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1049]

[1050] The title compound was obtained from(±)-trans-N-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and 5-chloro-6-fluoroindole-2-carboxylic acid in a similarmanner to Example 6.

[1051]¹H-NMR (DMSO-d₆) δ: 1.20-1.40(2H,m), 1.40-1.80(4H,m),1.80-2.00(2H,m), 2.87(3H,s), 3.01(2H,br.s), 3.30-3.80(2H,m),3.81-3.97(2H,m), 4.20-4.80(2H,m), 7.06(1H,s), 7.28(1H,d,J=10.0 Hz),7.86(1H,d,J=7.3 Hz), 8.32(1H,d,J=8.5 Hz), 8.59(1H,d,J=8.5 Hz),11.77(1H,s). MS (FAB) m/z: 490(M+H)⁺.

Example 15(±)-cis-N¹-[(5-Bromoindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1052]

[1053] The title compound was obtained from(±)-cis-N-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and 5-bromoindole-2-carboxylic acid in a similar manner toExample 6.

[1054]¹H-NMR (DMSO-d₆) δ: 1.43(2H,br.s), 1.61(4H,br.s), 1.80-2.10(2H,m),2.88(3H,s), 3.00-3.26(2H,m), 3.40(1H,br.s), 3.65(1H,br.s),4.22(1H,br.s), 4.26(1H,br.s), 4.41(1H,br.s), 4.67(1H,d,J=15.6 Hz),7.14(1H,s), 7.28(1H,d,J=8.7 Hz), 7.37(1H,d,J=8.7 Hz), 7.84(1H,.s),8.13(1H,br.s), 8.33-8.52(1H,m), 11.51(1H,br.s), 11.86(1H,s). MS (ESI)m/z: 515(M⁺).

Example 16(±)-cis-N¹-[(5-Ethynylindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[1055]

[1056] Triethylamine (6 ml), N,N-dimethylformamide (5 ml),trimethylsilylacetylene (0.250 ml) and palladium acetate (20 mg) wereadded to a tetrahydrofuran solution (2 ml) of(±)-cis-N¹-[(5-bromoindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(300 mg) and triphenylphosphine (70 mg) at room temperature. Afterstirring at 90° C. for 2 hours, the reaction mixture was allowed to coolto room temperature, and dichloromethane (20 ml) and a saturated aqueoussolution (30 ml) of sodium hydrogencarbonate were added to conductliquid separation. The resultant water layer was extracted withdichloromethane (3×10 ml), the organic layers were collected and driedover anhydrous sodium sulfate, and the solvent was distilled off underreduced pressure to obtain residue. The resultant residue was purifiedby preparative thin-layer chromatography on silica gel(dichloromethane:acetone:methanol=10:10:1) to obtain a mixture mainlycontaining(±)-cis-N¹-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-N²-[[5-(trimethylsilylethynyl)indol-2-yl]carbonyl]-1,2-cyclohexanediamineas a colorless solid. This product was dissolved in methanol (6 ml),potassium carbonate (120 mg) was added, and the mixture was stirred for1 hour. Dichloromethane (20 ml) and water (20 ml) were added to thereaction mixture to conduct liquid separation. The resultant water layerwas extracted with dichloromethane (2×15 ml), the organic layers werecollected and dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure. The resultant residue was purifiedby preparative thin-layer chromatography on silica gel(dichloromethane:acetone:methanol=10:10:1) and dissolved inwater-methanol-dichloromethane. The resultant solution was thenconcentrated to obtain the title compound (72 mg) as a pale yellowsolid.

[1057]¹H-NMR (CDCl₃) δ: 1.50-2.25(8H,m), 2.53(3H,s), 2.85(2H,br.s),2.93(2H,br.s), 3.01(1H,s), 3.74(1H,d,J=14.1 Hz), 3.77(1H,d,J=14.1 Hz),4.21(1H,br.s), 4.45(1H,br.s), 6.91(1H,s), 7.25-7.42(2H,m),7.61(1H,br.s), 7.80-7.97(2H,m), 9.72(1H,s). MS (FAB) m/z: 462(M+H)⁺.

Example 17(±)-cis-N¹-[(6-Bromonaphthalen-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1058]

[1059] The title compound was obtained from(±)-cis-N-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and 6-bromonaphthalene-2-carboxylic acid in a similarmanner to Example 6.

[1060]¹H-NMR (DMSO-d₆) δ: 1.45(2H,br.s), 1.62(4H,br.s), 1.96(2H,br.s),2.88(3H,s), 2.93-3.25(2H,m), 3.40(1H,br.s), 3.64(1H,br.s),4.25(2H,br.s), 4.41(1H,br.s), 4.66(1H,br.s), 7.72(1H,br.s),7.90(1H,br.s), 7.99(2H,br.s), 8.20-8.55(4H,m), 11.46(1H,br.s). MS (ESI)m/z: 526(M⁺,Br⁷⁹), 528(M⁺,Br⁸¹).

Example 18(±)-cis-N¹-[(6-Ethynylnaphthalen-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[1061]

[1062] The title compound was obtained from(±)-cis-N¹-[(6-bromonaphthalen-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminein a similar manner to Example 16.

[1063]¹H-NMR (CDCl₃) δ: 1.53-1.68(3H,m), 1.72(1H,br.s), 1.80(1H,br.s),1.93(2H,br.s), 2.17(1H,br.s), 2.59(3H,s), 2.94(2H,br.s),2.96-3.04(2H,m), 3.19(1H,s), 3.78-3.90(2H,m), 4.27(1H,br.s),4.48(1H,d,J=3.7 Hz), 7.55(1H,dd,J=8.4,1.3 Hz), 7.62(1H,d,J=7.8 Hz),7.71(1H,d,J=5.9 Hz), 7.83(1H,d,J=8.5 Hz), 7.87(1H,d,J=8.4 Hz),7.89(1H,dd,J=8.5,1.7 Hz), 8.02(1H,s), 8.31(1H,s). MS (FAB) m/z:473(M+H)⁺.

Example 19(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[4,5-d]pyridazin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1064]

[1065] The title compound was obtained from(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine andlithium5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[4,5-d]-pyridazine-2-carboxylatein a similar manner to Example 2.

[1066]¹H-NMR (DMSO-d₆) δ: 1.35-1.50(2H,m), 1.50-1.75(4H,m),1.80-2.10(2H,m), 2.70(3H,br.s), 2.79(3H,br.s), 4.10-4.70(6H,m),7.10-7.27(2H,m), 7.41(1H,d,J=8.8 Hz), 7.70(1H,s), 8.12(1H,d,J=6.8 Hz),8.47(1H,d,J=7.6 Hz), 11.85(1H,s). MS (FAB) m/z: 487(M+H)⁺.

Example 20(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)carbonyl]-1,2-cyclohexanediamine

[1067]

[1068] The title compound was obtained from(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and lithium6,7-dihydro-4H-pyrano[4,3-d]-thiazole-2-carboxylate in a similar mannerto Example 2.

[1069]¹H-NMR (DMSO-d₆) δ: 1.36-1.72(6H,m), 1.90-2.10(2H,m),2.80-2.87(2H,m), 3.93(2H,t,J=5.6 Hz), 4.20-4.32(2H,m), 4.81(2H,s),7.12(1H,s), 7.15(1H,dd, J=8.8,2.0 Hz), 7.41(1H,d,J=8.8 Hz),7.67(1H,d,J=1.7 Hz), 8.11(1H,d,J=6.6 Hz), 8.36(1H,d,J=8.3 Hz),11.78(1H,s). MS (FAB) m/z: 459(M+H)⁺.

Example 21(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1070]

[1071] The title compound was obtained from(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and lithium5-methyl-4,5,6,7-tetrahydro-thiazolo[4,5-c]pyridine-2-carboxylate in asimilar manner to Example 2.

[1072]¹H-NMR (DMSO-d₆) δ: 1.32-1.74(6H,m), 1.82-2.10(2H,m), 2.92(3H s),3.12-3.50(3H,m), 3.69(1H,br.s), 4.13-4.39(3H,m), 4.51(1H,br.s),7.10-7.19(2H,m), 7.41(1H,d,J=8.6 Hz), 7.68(1H,s), 8.10(1H,br.s),8.40(1H,br.s), 11.41(1H,br.s), 11.87(1H,s). MS (FAB) m/z: 472(M+H)⁺.

Example 22(±)-trans-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1073]

[1074] The title compound was obtained from(±)-trans-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and lithium5-methyl-4,5,6,7-tetrahydro-oxazolo[5,4-c]pyridine-2-carboxylate in asimilar manner to Example 2.

[1075]¹H-NMR (DMSO-d₆) δ: 1.23-1.39(2H,m), 1.40-1.81(4H,m),1.82-1.98(2H,m), 2.60-3.00(5H,m), 3.20-3.70(2H,m), 3.87-3.96(1H,m),3.98-4.10(1H,m), 4.12-4.70(2H,m), 7.04(1H,d,J=1.5 Hz),7.12(1H,dd,J=8.8,2.0 Hz), 7.38(1H,d,J=8.8 Hz), 7.65(1H,d,J=2.0 Hz),8.33(1H,d,J=8.6 Hz), 8.72(1H,d,J=8.6 Hz), 11.61(1H,br.s), 11.72(1H,s).MS (FAB) m/z: 456(M+H)⁺.

Example 23(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1076]

[1077] The title compound was obtained from(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and lithium5-methyl-4,5,6,7-tetrahydro-oxazolo[5,4-c]pyridine-2-carboxylate in asimilar manner to Example 2.

[1078]¹H-NMR (DMSO-d₆) δ: 1.33-1.72(6H,m), 1.86-2.06(2H,m),2.70-3.05(5H,m), 3.30-3.77(2H,m), 4.17-4.32(2H,m), 4.33-4.70(2H,m),7.12-7.20(2H,m), 7.41(1H,d,J=8.8 Hz), 7.68(1H,s), 8.08(1H,d,J=6.9 Hz),8.54(1H,br.s), 11.61(1H,br.s), 11.85(1H,s). MS (FAB) m/z: 456(M+H)⁺.

Example 24(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1079]

[1080] The title compound was obtained from(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and lithium6-methyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-2-carboxylate in asimilar manner to Example 2.

[1081]¹H-NMR (DMSO-d₆) δ: 1.41(2H,br.s), 1.51-1.74(4H,m), 1.99(2H,br.s),2.85-3.10(5H,m), 3.25-3.50(1H,m), 3.60(1H,br.s), 4.10-4.37(3H,m),4.53-4.67(1H,m), 7.15(1H,dd,J=8.6,2.0 Hz), 7.23(1H,s), 7.41(1H,d,J=8.6Hz), 7.65(1H,s), 7.80(1H,s), 8.10-8.30(2H,m), 10.84(1H,br.s), 11.90 (1H,s). MS (FAB) m/z: 471(M+H)⁺.

Example 25(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1082]

[1083] The title compound was obtained by dissolving(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride (164 mg),5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylicacid (WO94/21599) (140 mg) and 1-hydroxy-benzotriazole monohydrate (76mg) in N,N-dimethyl-formamide (20 ml), causing1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (192 mg) toreact as a condensing agent and then conducting a treatment withhydrochloric acid to deprotect in a similar manner to Example 2.

[1084]¹H-NMR (DMSO-d₆) δ: 1.42(2H,br.s), 1.56-1.76(4H,m),1.98-2.11(2H,m), 3.04(2H,br.s), 3.32-3.45(2H,m), 4.15(3H,br.s),4.26(1H,br.s), 7.14(1H,dd,J=8.8,2.0 Hz), 7.23(1H,s), 7.41(1H,d,J=8.8Hz), 7.62(1H,s), 7.77(1H,s), 8.18-8.30(2H,m), 9.42(2H,br.s),11.92(1H,s). MS (FAB) m/z: 457(M+H)⁺.

Example 26(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1085]

[1086] (±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride (171 mg) was suspended in dichloromethane (10 ml), andtriethylamine (0.104 ml) was added to stir the mixture at roomtemperature for 10 minutes. After acetic acid (0.059 ml) was added tothe reaction mixture, a 35% aqueous formaldehyde solution (0.070 ml) andsodium triacetoxyborohydride (118 mg) were added, and the mixture wasstirred at room temperature for 30 minutes. After a 1N aqueous solution(3 ml) of sodium hydroxide was added to the reaction mixture, water wasadded to conduct liquid separation. After the resultant organic layerwas dried over anhydrous sodium sulfate, the solvent was then distilledoff under reduced pressure, and the residue was purified by columnchromatography on silica gel (dichloromethane:methanol=50:3) to obtain acolorless foamy substance. This substance was suspended in 1Nhydrochloric acid, and the suspension was concentrated under reducedpressure to obtain the title compound (85 mg) as a colorless foamysubstance.

[1087]¹H-NMR (DMSO-d₆) δ: 1.40(2H,br.s), 1.50-1.71(4H,m),1.97-2.05(2H,m), 2.87(3H,s), 2.98-3.20(1H,m), 3.30-3.38(2H,m),3.54-3.70(1H,m), 4.05-4.42(4H,m), 7.14(1H,d,J=8.6 Hz), 7.23(1H,s),7.40(1H,d,J=8.6 Hz), 7.63(1H,s), 7.77(1H,s), 8.17-8.27(2H,m),10.83(1H,br.s), 11.92(1H,s). MS (FAB) m/z: 471(M+H)⁺.

Example 27cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[[5-(N,N-dimethylamino)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1088]

[1089] The title compound was obtained from(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and lithium[5-(N,N-dimethylamino)-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxylatein a similar manner to Example 2.

[1090]¹H-NMR (DMSO-d₆) δ: 1.44(2H,br.s), 1.52-1.68(4H,m),1.87-2.08(3H,m), 2.30-2.40(1H,m), 2.65-2.75(1H,m), 2.77(6H,s),2.95-3.17(2H,m), 3.30-3.70(2H,m), 4.15-4.30(2H,m), 7.10-7.20(2H,m),7.41(1H,d,J=8.6 Hz), 7.69(1H,s), 8.11(1H,d,J=5.1 Hz), 8.34(1H,d,J=8.1Hz), 10.95(1H,br.s), 11.83(1H,s). MS (FAB) m/z: 500(M+H)⁺.

Example 28(±)-cis-N¹-[(6-Chloroindol-2-yl)carbonyl]-N²-[[5-(4-pyridyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1091]

[1092] n-Butyllithium (1.60N hexane solution, 0.704 ml) was addeddropwise to a solution of5-(4-pyridyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (204 mg) intetrahydrofuran 3 ml) at −78° C. and the mixture was stirred at 0° C.for 30 minutes. After the reaction mixture was cooled to −78° C. again,it was heated to room temperature in 20 minutes while blowing carbondioxide, and the reaction mixture was concentrated under reducedpressure.(±)-cis-N-[(5-Chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride (400 mg), 1-hydroxy-benzotriazole monohydrate (254 mg),1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (360 mg)and diisopropylamine (0.491 ml) were added to a solution of theresultant residue in N,N-dimethylformamide (6 ml) at room temperature.After stirring for 3 days, the reaction mixture was concentrated underreduced pressure, and dichloromethane (30 ml), a saturated aqueoussolution (100 ml) of sodium hydrogencarbonate and water (100 ml) wereadded to the residue to conduct liquid separation. The resultant waterlayer was extracted with dichloromethane (4×15 ml), the organic layerswere collected and dried over anhydrous sodium sulfate, and the solventwas distilled off under reduced pressure. The resultant residue waspurified by column chromatography on silica gel(dichloromethane:methanol=20:1→10:1) and dissolved in 1N hydrochloricacid-methanol-dichloromethane. The resultant solution was thenconcentrated to obtain the title compound (245 mg) as a pale yellowsolid.

[1093]¹H-NMR (DMSO-d₆) δ: 1.42(2H,br.s), 1.60(4H,br.s), 1.84-1.94(1H,m),1.94-2.08(1H,m), 2.97(2H,br.s), 3.97-4.13(2H,m), 4.19(1H,br.s),4.27(1H,br.s), 5.03(2H,s), 7.13(1H,br.s), 7.16(1H,dd,J=8.8,2.0 Hz),7.32(2H,br.s), 7.40(1H,d,J=8.8 Hz), 7.68(1H,d,J=2.0 Hz),8.15(1H,br,J=7.3 Hz), 8.31(2H,d,J=5.9 Hz), 8.39(1H,d,J=8.1 Hz),11.90(1H,s), 14.03(1H,br.s). MS (ESI) m/z: 535(M+H)⁺.

Example 29(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[4-(4-pyridyl)benzoyl]-1,2-cyclohexanediaminehydrochloride

[1094]

[1095] The title compound was obtained from(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and 4-(4-pyridyl)benzoic acid hydrochloride in a similarmanner to Example 2.

[1096]¹H-NMR (DMSO-d₆) δ: 1.40-1.52(2H,m), 1.60-1.80(4H,m),1.96-2.10(2H,m), 4.24-4.39(2H,m), 7.15(1H,dd,J=8.8,2.0 Hz), 7.21(1H,s),7.40(1H,d,J=8.8 Hz), 7.64(1H,d,J=2.0 Hz), 8.06(4H,s), 8.18(1H,J=7.3 Hz),8.34-8.42(3H,m), 8.94(2H,d,J=6.9 Hz), 11.91(1H,s). MS (FAB) m/z:473(M+H)⁺.

Example 30(±)-4-[4-[N-[cis-2-[[(5-Chloroindol-2-yl)carbonyl]-amino]cyclohexyl]carbamoyl]phenyl]pyridineN-oxide

[1097]

[1098] The title compound was obtained from(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and 4-(4-carboxyphenyl)pyridine N-oxide in a similarmanner to Example 2.

[1099]¹H-NMR (DMSO-d₆) δ: 1.40-1.52(2H,m), 1.60-1.80(4H,m),1.88-2.00(2H,m), 4.21-4.36(2H,m), 7.12-7.18(2H,m), 7.41(1H,d,J=8.6 Hz),7.66(1H,s), 7.80-7.87(4H,m), 7.91(2H,d,J=8.3 Hz), 8.01(1H,d,J=7.6 Hz),8.09(1H,d,J=7.3 Hz), 8.27(2H,d,J=6.6 Hz), 11.79(1H,s). MS (FAB) m/z:489(M+H)⁺.

Example 31(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[4-(2-pyridyl)benzoyl]-1,2-cyclohexanediaminehydrochloride

[1100]

[1101] The title compound was obtained from(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and 4-(2-pyridyl)benzoic acid (Japanese Patent ApplicationLaid-Open No. 2000-119253) in a similar manner to Example 2.

[1102]¹H-NMR (DMSO-d₆) δ: 1.39-1.51(2H,m), 1.60-1.80(4H,m),1.89-2.00(2H,m), 4.24-4.38(2H,m), 7.12-7.16(2H,m), 7.36-7.39(1H,m),7.42(1H,d,J=8.8 Hz), 7.66(1H,d,J=2.0 Hz), 7.87-7.90(1H,m),7.92(2H,d,J=8.3 Hz), 7.98-8.11(3H,m), 8.15(2H,d,J=8.3 Hz),8.69(1H,d,J=4.6 Hz), 11.80(1H,s). MS (FAB) m/z: 473(M+H)⁺.

Example 32(±)-2-[4-[N-[cis-2-[[(5-Chloroindol-2-yl)carbonyl]-amino]cyclohexyl]carbamoyl]phenyl]pyridineN-oxide

[1103]

[1104] The title compound was obtained from(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and 2-(4-carboxyphenyl)pyridine N-oxide in a similarmanner to Example 2.

[1105]¹H-NMR (DMSO-d₆) δ: 1.39-1.51(2H,m), 1.60-1.79(4H,m),1.89-2.00(2H,m), 4.23-4.37(2H,m), 7.12-7.17(2H,m), 7.39-7.43(3H,m),7.61-7.64(1H,m), 7.67(1H,d,J=2.0 Hz), 7.89(4H,s), 8.00-8.06(1H.m),8.08-8.02(1H,m), 8.32-8.35(1H,m), 11.79(1H,s). MS (FAB) m/z: 489(M+H)⁺.

Example 33(±)-trans-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[[5-(4-pyridyl)thiazol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1106]

[1107] The title compound was obtained from(±)-trans-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine andlithium 5(4-pyridyl)thiazole-2-carboxylate in a similar manner toExample 2.

[1108]¹H-NMR (DMSO-d₆) δ: 1.44(2H,br.s), 1.65(4H,br.s), 1.85-2.06(2H,m),4.23(1H,br.s), 4.30(1H,br.s), 7.14-7.23(2H,m), 7.41(1H,d,J=8.8 Hz),7.69(1H,s), 8.04-8.13(2H,m), 8.13(1H,d,J=8.8 Hz), 8.59(1H,d,J=8.0 Hz),8.75-8.87(3H,m), 11.83(1H,s). MS (ESI) m/z: 480(M+H)⁺.

Example 34 (±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N¹-methyl-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1109]

[1110] The title compound was obtained from(±)-cis-N¹-[(5-chloroindol-2-yl)carbonyl]-N¹-methyl-1,2-cyclohexanediamine and lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in asimilar manner to Example 2.

[1111]¹H-NMR (DMSO-d₆) δ: 1.42-1.90(7H,m), 2.23-2.32(1H,m), 2.90(3H,s),3.11(3H,br.s), 3.19(2H,br.s), 3.45-3.67(2H,brm), 4.41-4.72(4H,m),6.76(1H,s), 7.17(1H,dd,J=8.8,2.0 Hz), 7.43(1H,d,J=8.8 Hz),7.64(1H,br.s), 8.52(1H,br,J=8.5 Hz), 11.46(1H,br.s), 11.71(1H,s). MS(ESI) m/z: 500(M+H)⁺.

Example 35(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-methyl-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1112]

[1113] A saturated ethanol solution (5 ml) of hydrochloric acid wasadded to(±)-cis-N¹-(tert-butoxycarbonyl)-N²-methyl-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(324 mg), the mixture was stirred at room temperature for 30 minutes,and the solvent was distilled off under reduced pressure. The residuewas dissolved in N,N-dimethylformamide (5 ml), and triethylamine (1 ml),5-chloroindole-2-carboxylic acid (279 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (458 mg) and1-hydroxybenzotriazole monohydrate (108 mg) were added to the solution.The resultant mixture was stirred at room temperature for 7 days. Thesolvent was distilled off under reduced pressure using a pump, anddichloromethane and a saturated aqueous solution of sodiumhydrogencarbonate were added to the residue to conduct liquidseparation. The resultant organic layer was dried over anhydrous sodiumsulfate, and the solvent was then distilled off under reduced pressure.The resultant residue was purified by flash column chromatography onsilica gel (dichloromethane:methanol=93:7) to obtain a pale yellow solid(176 mg). After this product was dissolved in methanol (5 ml), and a 1Nethanol solution (362 μl) of hydrochloric acid was added, the solventwas concentrated under reduced pressure, and ethyl acetate was added tothe residue. Precipitate thus formed was collected by filtration toobtain the title compound (164 mg) as a pale yellow solid.

[1114]¹H-NMR (DMSO-d₆) δ: 1.43-1.90(7H,m), 2.26-2.31(1H,m), 2.90(3H,s),3.11-3.19(5H,m), 3.48-3.68(2H,m), 4.42-4.72(4H,m), 6.76(1H,d,J=1.5 Hz),7.17(1H,dd,J=8.8,2.1 Hz), 7.43(1H,d,J=8.8 Hz), 7.64(1H,br.s),8.52(1H,br,J=7.6 Hz), 11.45(1H,br.s), 11.71(1H,br.s). MS (ESI) m/z:486(M+H)⁺.

Example 36(±)-trans-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cycloheptanediaminehydrochloride

[1115]

[1116] The title compound was obtained from(±)-trans-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cycloheptanediamine andlithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxylate in asimilar manner to Example 2.

[1117]¹H-NMR (DMSO-d₆) δ: 1.51-1.55(4H,m), 1.75-1.80(6H,m), 2.88(3H,s),3.12(1H,br.s), 3.35-3.63(4H,m), 4.10-4.13(1H,m), 4.29-4.61(2H,m),7.06(1H,s), 7.14(1H,dd,J=8.8,2.0 Hz), 7.39(1H,d,J=8.8 Hz),7.67(1H,d,J=2.0 Hz), 8.46(1H,d,J=8.3 Hz), 8.77(1H,d,J=8.3 Hz),11.21-11.35(1H,m), 11.71(1H,s). MS (ESI) m/z: 486(M+H)⁺.

Example 37(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclooctanediaminehydrochloride

[1118]

[1119] The title compound was obtained from(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclooctanediamine andlithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxylate in asimilar manner to Example 2.

[1120]¹H-NMR (DMSO-d₆) δ: 1.61-2.06(12H,m), 2.90(3H,s), 3.08-3.17(2H,m),3.43-3.45(1H,m), 3.67(1H,br.s), 4.43(3H,br.s), 4.67(1H,br.s),7.16-7.18(2H,m), 7.42(1H,d,J=8.8 Hz), 7.70(1H,s), 8.24(1H,br.s),8.58(1H,d,J=8.3 Hz), 11.43,11.63(1H,each br.s), 11.80(1H,s). MS (ESI)m/z: 500(M+H)⁺.

Example 38N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-ethylenediaminehydrochloride

[1121]

[1122] The title compound was obtained fromN¹-tert-butoxycarbonyl-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-ethylenediaminein a similar manner to Example 35.

[1123]¹H-NMR (DMSO-d₆) δ: 2.91(3H,s), 3.17(2H,br.s), 3.47(4H,br.s),3.56(2H,br.s), 4.53(2H,br.s), 7.08(1H,d,J=1.7 Hz), 7.17(1H,dd,J=8.8,2.0Hz), 7.42(1H,d,J=8.8 Hz), 7.69(1H,d,J=2.0 Hz), 8.69(1H,br.s),9.00(1H,br.s), 11.62(1H,br.s), 11.79(1H,br.s). MS (FAB) m/z: 418(M+H)⁺.

Example 39N¹-[(5-Chloroindol-2-yl)carbonyl]-N¹-methyl-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-ethylenediaminehydrochloride

[1124]

[1125] The title compound was obtained fromN¹-methyl-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-ethylenediamineand 5-chloroindole-2-carboxylic acid in a similar manner to Example 2.

[1126]¹H-NMR (DMSO-d₆) δ: 2.91(3H,s), 3.15-3.73(11H,m), 4.46-4.61(2H,m),6.86(1H,d,J=2.0 Hz), 7.18(1H,dd,J=8.8,2.0 Hz), 7.41(1H,d,J=8.8 Hz),7.65(1H,br.s), 9.06(1H,t,J=5.7 Hz), 11.48(1H,br.s), 11.72(1H,br.s). MS(ESI) m/z: 432(M+H)⁺.

Example 40

[1127]N¹-[(5-Chloroindol-2-yl)sulfonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-ethylenediamine hydrochloride

[1128] The title compound was obtained by eliminating the tert-butoxygroup of N¹-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-N²-(tert-butoxycarbonyl)-1,2-ethylenediamine and then reacting it withlithium 5-4methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in asimilar manner to Example 35.

[1129]¹H-NMR (DMSO-d₆) δ: 2.92(3H,m), 3.06-3.12(4H,m), 3.31-3.37(2H,m),3.44-3.74(2H,m), 4.38-4.75(2H,m), 6.92(1H,,d,J=1.2 Hz),7.27(1H,dd,J=8.8,1.7 Hz), 7.43(1H,d,J=8.8 Hz), 7.70(1H,d,J=1.7 Hz),7.90(1H,t,J=5.8 Hz), 8.81(1H,t,J=5.8 Hz), 11.25(1H,br.s),12.14(1H,br.s). MS (FAB) m/z: 454(M+H)⁺.

Example 41(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1130]

[1131] 5-Methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole (155 mg) wasdissolved in tetrahydrofuran (7 ml) in an argon atmosphere, and thesolution was cooled to −78° C., to which tert-butyllithium (1.54Npentane solution, 0.792 ml) was added dropwise. The reaction mixture wasstirred for 1 hour under ice cooling and cooled again to −78° C. Afterblowing carbon dioxide into the reaction mixture for 20 minutes, it washeated to room temperature. The reaction mixture was concentrated underreduced pressure to obtain crude lithium5-methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-2-carboxylate. Thisproduct was dissolved in N,N-dimethylformamide (20 ml), and to thissolution, were added(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride (364 mg), 1-hydroxybenzotriazole monohydrate (150 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (426 mg).After the resultant mixture was stirred overnight, the solution wasconcentrated, and dichloromethane and a saturated aqueous solution ofsodium hydrogencarbonate were added to the residue to conduct liquidseparation. The resultant organic layer was dried over anhydrous sodiumsulfate, and the solvent was then distilled off under reduced pressure.The resultant residue was purified by column chromatography on silicagel (methanol:dichloromethane=7:93). A 1N ethanol solution ofhydrochloric acid and ethyl acetate were added to the thus-obtainedproduct, and powder deposited was collected by filtration to obtain thetitle compound (343 mg) as colorless powder.

[1132]¹H-NMR (DMSO-d₆) δ: 1.35-1.53(2H,m), 1.64(4H,br.s),1.82-2.05(2H,m), 3.03(3H,br.s), 4.15-5.00(6H,m), 7.15(1H,d,J=1.9 Hz),7.18(1H,dd,J=8.7,1.9 Hz), 7.42(1H,d,J=8.7 Hz), 7.71(1H,d,J=1.9 Hz),8.11(1H,d,J=7.6 Hz), 8.46(1H,d,J=7.1 Hz), 11.85(1H,br.s),12.26(1H,br.s). MS (FAB) m/z: 458(M+H)⁺.

Example 42(1R,2R)-N¹-(5-Chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride

[1133]

[1134] The title compound was obtained from(1R,2R)-N-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride in a similar manner to Example 6. The absolute structurewas determined by X-ray analysis.

[1135] MS (ESI) m/z: 458(M+H)⁺. [α]_(D)−181.59° (C=1.02, dimethylsulfoxide).

Example 43(±)-trans-N¹-[(5-Bromoindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride

[1136]

[1137] The title compound was obtained from(±)-trans-N-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride and 5-bromoindole-2-carboxylic acid in a similar manner toExample 6.

[1138]¹H-NMR (DMSO-d₆) δ: 1.65-1.76(4H,m), 2.00-2.03(2H,m), 2.91(3H,s),3.13-3.19(2H,br.s), 3.47(1H,br.s), 3.68(1H,br.s), 4.30-4.67(4H,m),7.11(1H,d,J=1.5 Hz), 7.27(1H,dd,J=8.8,2.0 Hz), 7.35(1H,d,J=8.8 Hz),7.84(1H,d,J=1.5 Hz), 8.56(1H,d,J=8.5 Hz), 8.93(1H,d,J=8.8 Hz),11.44(1H,br.s), 11.78(1H,br.s). MS (ESI) m/z: 502(M+H)⁺.

Example 44(±)-trans-N¹-(5-Chloroindol-2-yl)carbonyl]-N²-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride

[1139]

[1140] The title compound was obtained by subjecting a product obtainedby the reaction of(±)-trans-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclopentanediamine withlithium5-tert-butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carboxylateto a deprotecting treatment in a similar manner to Example 2.

[1141]¹H-NMR (DMSO-d₆) δ: 1.60-1.82(4H,m), 1.91-2.15(2H,m), 3.08(2H,s),3.37-3.49(2H,m), 4.28-4.56(4H,m), 7.13(1H,s), 7.15(1H,d,J=8.8 Hz),7.40(1H,d,J=8.8 Hz), 7.69(1H,s), 8.61(1H,d,J=8.3 Hz), 8.88(1H,d,J=8.3Hz), 10.05(2H,br.s), 11.82(1H,s). MS (FAB) m/z: 444(M+H)⁺.

Example 45 (±)-trans-N¹-(5-Chloroindol-2-yl)carbonyl]-N²-[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride

[1142]

[1143](±)-trans-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride (30 mg) was suspended in dichloromethane (20 ml), andtriethylamine (260 μl) was added to stir the mixture at room temperaturefor 15 minutes. Acetic acid (179 μl) and acetone (920 μl) were added tothe reaction mixture, and the resultant mixture was stirred at roomtemperature for 2 minutes. Sodium triacetoxyborohydride (796 mg) wasadded to the reaction mixture to stir them at room temperature for 5hours. A 1N aqueous solution (10 ml) of sodium hydroxide was added tothe reaction mixture to conduct liquid separation. The resultant organiclayer was dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure. The residue was purified by columnchromatography on silica gel (dichloromethane:methanol=100:3) to obtaina colorless foamy substance. This product was dissolved indichloromethane, and a 1N ethanol solution (1 ml) of hydrochloric acidwas added. The solution was concentrated under reduced pressure toobtain the title compound (205 mg) as a pale yellow foamy substance.

[1144]¹H-NMR (DMSO-d₆) δ: 1.27-1.39(6H,m), 1.58-1.80(4H,m),1.95-2.10(2H,m), 3.00-3.12(1H,m), 3.25-3.45(2H,m), 3.59-3.77(2H,m),4.25-4.39(1H,m), 4.40-4.55(2H,m), 4.57-4.65(1H,m), 7.10(1H,s),7.14(1H,d,J=8.8 Hz), 7.38(1H,d,J=8.8 Hz), 7.68(1H,s), 8.56(1H,d,J=8.8Hz), 8.90(1H,d,J=8.8 Hz), 11.39(1H,br.s), 11.76(0.5H,s), 11.80(0.5H,s).MS (FAB) m/z: 486(M+H)⁺.

Example 46 (±) -trans-N¹-(5-Chloroindol-2-yl)carbonyl]-N²-[[5-(2,3,5,6-tetrahydro-4H-pyran-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-1,2-cyclopentanediaminehydrochloride

[1145]

[1146] The title compound was obtained from(±)-trans-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride by using tetrahydro-4H-pyran-4-one in place of acetone inExample 45.

[1147]¹H-NMR (DMSO-d₆) δ: 1.60-2.20(10H,m), 3.08-3.18(1H,m),3.21-3.70(5H,m), 3.72-3.91(1H,m), 3.93-4.04(2H,m), 4.27-4.42(1H,m),4.45-4.60(2H,m), 4.62-4.77(1H,m), 7.12(1H,s), 7.15(1H,dd,J=8.8,2.0 Hz),7.39(1H,d,J=8.8 Hz), 7.69(1H,d,J=1.7 Hz), 8.56(1H,d,J=8.3 Hz),8.91(1H,d,J=8.3 Hz), 11.77(1H,s), 11.79(1H,s). MS (FAB) m/z: 528(M+H)⁺.

Example 47(±)-trans-N¹-(5-Chloroindol-2-yl)carbonyl]-N²-[(5-cyclopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride

[1148]

[1149] Acetic acid (0.1 ml), molecular sieve 4 A powder (1 g) and[(1-ethoxycyclopropyl)oxy]trimethylsilane (0.173 ml) and successivelysodium cyanoborohydride (43.2 mg) were added to a solution of(±)-trans-N¹-(5-chloroindol-2-yl)carbonyl]-N²-[(4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride (82.8 mg) in methanol (30 ml), and the mixture was heatedunder reflux for 18.5 hours. After allowing the reaction mixture tocool, it was filtered, and the filtrate was concentrated under reducedpressure. The residue was dissolved in ethyl acetate, the solution waswashed with a 2N aqueous solution of sodium hydroxide and saturatedsaline and dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (methanol:dichloromethane=3:97) toobtain a pale yellow amorphous substance (52 mg). A mixture of ethanoland hydrochloric acid was added to this product and then methanol anddichloromethane were added to obtain the title compound as solid.

[1150]¹H-NMR (DMSO-d₆) δ: 0.86(2H,d,J=6.8 Hz), 1.16-1.23(3H,m),1.62-1.76(4H,m), 2.01-2.04(2H,m), 3.00(1H,br), 3.19(2H,br), 3.68(2H,br),4.30-4.34(1H,m), 4.47-4.51(1H,m), 4.64(1H,br), 7.10(1H,d,J=1.4 Hz),7.14(1H,dd,J=8.7,2.1 Hz), 7.39(1H,d,J=8.7 Hz), 7.67(1H,d,J=1.9 Hz),8.53(1H,d,J=8.3 Hz), 8.89(1H,d,J=8.5 Hz), 11.74(1H,s). MS (FAB) m/z:484(M+H)⁺.

Example 48(±)-trans-N¹-(5-Chloroindol-2-yl)carbonyl]-N²-[[5-(1-methylcyclopropyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl]carbonyl]-1,2-cyclopentanediaminehydrochloride

[1151]

[1152] The title compound was obtained from(±)-trans-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride and lithium5-(1-methylcyclopropyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylatein a similar manner to Example 2.

[1153]¹H-NMR (DMSO-d₆) δ: 0.81(2H,br.s), 1.20-1.55(5H,br),1.55-1.80(4H,m), 1.95-2.12(2H,m), 3.05-3.40(2H,br), 3.60-3.80(2H,br),4.25-4.80(4H,m), 7.10(1H,s), 7.16(1H,d,J=8.8 Hz), 7.39(1H,d,J=8.8 Hz),7.69(1H,s), 8.53(1H,d,J=8.6 Hz), 8.85-8.95(1H,m), 10.60-10.90(1H,br),11.73(1H,br.s). MS (FAB) m/z: 498(M+H)⁺.

Example 49(±)-trans-N¹-[[5-(tert-Butyl)-4,6-dihydro-5H-pyrrolo-[3,4-d]thiazol-2-yl]carbonyl]-N²-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride

[1154]

[1155] The title compound was obtained from(±)-trans-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride and lithium5-(tert-butyl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-2-carboxylate in asimilar manner to Example 2.

[1156]¹H-NMR (DMSO-d₆) δ: 1.40(9H,s), 1.60-1.80(4H,m), 1.95-2.10(2H,m),4.25-4.40(1H,m), 4.40-4.55(2H,m), 4.60-4.85(3H,m), 7.11(1H,s),7.16(1H,d,J=8.8 Hz), 7.39(1H,d,J=8.8 Hz), 7.69(1H,s), 8.54(1H,d,J=8.5Hz), 8.95-9.05(1H,m), 11.70-11.80(1H,m), 12.45-12.65(1H,m). MS (FAB)m/z: 486(M+H)⁺.

Example 50(±)-trans-N¹-[[5-(tert-Butyl)-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl]carbonyl]-N²-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride

[1157]

[1158] The title compound was obtained from(±)-trans-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride and lithium(5-tert-butyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylatein a similar manner to Example 2.

[1159]¹H-NMR (DMSO-d₆) δ: 1.43(9H,s), 1.55-1.85(4H,m), 1.95-2.10(2H,m),3.05-3.40(3H,m), 3.85-3.95(1H,m), 4.25-4.40(1H,m) ,4.40-4.55(2H,m),4.70-4.85(1H,m), 7.11(1H,s), 7.16(1H,dd,J=8.8,2.0 Hz), 7.39(1H,d,J=8.8Hz), 7.70(1H,d,J=2.0 Hz), 8.50-8.58(1H,m), 8.92(1H,d,J=8.5 Hz),10.78(1H,br.s), 11.73-11.79(1H,m). MS (FAB) m/z: 500(M+H)⁺.

Example 51 (±)-trans-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[[5-(1,1-dimethyl-2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl]carbonyl]-1,2-cyclopentanediaminehydrochloride

[1160]

[1161] A 1 M tetrahydrofuran solution (5.0 ml) of tetrabutylammoniumfluoride was added to(±)-trans-N¹-[[5-[2-(tert-butyldiphenylsilyloxy)-1,1-dimethylethyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-N²-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclopentanediamine(757 mg) obtained by the reaction of(±)-trans-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride (393 mg) with lithium5-[2-(tert-butyldiphenylsilyloxy)-1,1-dimethylethyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate(812 mg) in a similar manner to Example 2, and the mixture was stirredovernight at room temperature. Dichloromethane and saturated saline wereadded to the reaction mixture to separate an organic layer, and theorganic layer was dried over anhydrous magnesium sulfate. The solventwas distilled off, and the residue was purified by column chromatographyon silica gel (methanol:dichloromethane=1:19) to obtain yellow powder.This product was dissolved in dichloromethane, and a 1N ethanol solutionof hydrochloric acid and ethyl acetate were added to the solution. Afterthe mixture was concentrated, ethyl acetate was added to solidify theresidue, thereby obtaining the title compound (328 mg) as colorlesspowder.

[1162]¹H-NMR (DMSO-d₆) δ: 1.30(3H,s), 1.39(3H,s), 1.55-1.80(4H,m),1.95-2.10(2H,m), 3.05-3.95(6H,m), 4.75-4.25(4H,m), 5.80(1H,br.s),7.10(1H,s), 7.16(1H,d,J=8.6 Hz), 7.39(1H,d,J=8.6 Hz), 7.69(1H,s),8.52(1H,d,J=8.3 Hz), 8.90(1H,d,J=8.3 Hz), 9.92(1H,br.s), 11.72(1H,br.s).MS (FAB) m/z: 516(M+H)⁺.

Example 52 (±)-trans-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-ethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride

[1163]

[1164] (±)-trans-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride (500 mg) was dissolved in N,N-dimethylformamide (10 ml),and triethylamine (576 μl) and ethyl iodide (329 μl) were added to stirthe mixture overnight at room temperature. The reaction mixture wasconcentrated under reduced pressure, and water was added to the residueto collect insoluble matter by filtration. This product was purified bycolumn chromatography on silica gel (dichloromethane:methanol=100:3) toobtain a pale brown foamy substance. This substance was suspended in 1Nhydrochloric acid (2 ml), and the suspension was concentrated underreduced pressure to obtain the title compound (180 mg) as a pale yellowfoamy substance.

[1165]¹H-NMR (DMSO-d₆) δ: 1.32(3H,t,J=7.1 Hz), 1.60-1.80(4H,m),1.96-2.10(2H,m), 3.20-3.39(5H,m), 3.70-3.80(1H,m), 4.26-4.58(3H,m),4.68-4.79(1H,m), 7.11(1H,s), 7.15(1H,dd,J=8.8,2.0 Hz), 7.39(1H,d,J=8.8Hz), 7.69(1H,d,J=1.5 Hz), 8.55(1H,d,J=8.5 Hz), 8.92(1H,d,J=8.5 Hz),11.38(1H,br.s), 11.70-11.80(1H,m). MS (FAB) m/z: 472(M+H)⁺.

Example 53(±)-trans-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[[5-(2-methoxyethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-1,2-cyclopentanediaminehydrochloride

[1166]

[1167] The title compound was obtained from(±)-trans-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride and 2-methoxyethyl bromide in a similar manner to Example52.

[1168]¹H-NMR (DMSO-d₆) δ: 1.58-1.80(4H,m), 1.96-2.09(2H,m),3.05-3.28(2H,m), 3.31(3H,s), 3.41-3.57(3H,m), 3.70-3.85(3H,m),4.26-4.38(1H,m), 4.40-4.57(2H,m), 4.66-4.80(1H,m), 7.10(1H,s),7.15(1H,d,J=8.8 Hz), 7.38(1H,d,J=8.8 Hz), 7.69(1H,s), 8.56(1H,d,J=8.3Hz), 8.93(1H,d,J=8.3 Hz), 11.20(1H,br.s), 11.77(1H,s).

[1169] MS (FAB) m/z: 502(M+H)⁺.

Example 54(±)-trans-N¹-[[5-(tert-Butoxycarbonylmethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-N²-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclopentanediamine

[1170]

[1171] The title compound was obtained from(±)-trans-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride and tert-butyl bromoacetate in a similar manner to Example52.

[1172]¹H-NMR (CDCl₃) δ: 1.47(9H,s), 1.60-1.95(4H,m), 2.19-2.28(1H,m),2.45-2.55(1H,m), 2.87-3.07(4H,m), 3.36(2H,s), 3.88(1H,d,J=15.4 Hz),3.97(1H,d,J=15.4 Hz), 4.09-4.18(1H,m), 4.38-4.49(1H,m), 6.90(1H,d,J=2.0Hz), 7.18(1H,dd,J=8.8,2.0 Hz), 7.31(1H,d,J=8.8 Hz), 7.49(1H,d,J=7.8 Hz),7.61(1H,s), 7.71(1H,d,J=5.6 Hz), 9.57(1H,s). MS (FAB) m/z: 558(M+H)⁺.

Example 55(±)-trans-N¹-[[5-(Carboxymethyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-N²-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclopentanediamine

[1173]

[1174] The compound (170 mg) obtained in Example 54 was dissolved indichloromethane (1 ml), and trifluoroacetic acid (5 ml) was added tostir the mixture at room temperature for 2 hours. The reaction mixturewas concentrated under reduced pressure, and diethyl ether was added tothe residue to collect precipitate deposited by filtration, therebyobtaining the title compound (127 mg) as a colorless foamy substance.

[1175]¹H-NMR (DMSO-d₆) δ: 1.65-1.80(4H,m), 2.00-2.12(2H,m),3.02-3.10(2H,m), 3.40-3.55(2H,m), 3.98-4.08(2H,m), 4.30-4.59(4H,m),7.10(1H,s), 7.17(1H,dd,J=8.6,2.0 Hz), 7.39(1H,d,J=8.6 Hz), 7.69(1H,s),8.53(1H,d,J=8.6 Hz), 8.99(1H,d,J=9.0 Hz), 11.73(1H,s). MS (FAB) m/z:502(M+H)⁺.

Example 56(1R*,2R*)-N¹-[(5-Chloroindol-2-yl)carbonyl]-4-methoxycarbonyl-N²-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride (Stereoisomer A and Stereoisomer B)

[1176]

[1177](1R*,2R*)-N¹-[(5-Chloroindol-2-yl)carbonyl]-4-methoxycarbonyl-1,2-cyclopentanediamine(mixture of stereoisomers) (3.42 g) was dissolved inN,N-dimethylformamide (20 ml), and lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate (3.12g), 1-hydroxybenzotriazole monohydrate (689 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.89 g)were added to stir the mixture overnight at room temperature. Thereaction mixture was concentrated under reduced pressure, and asaturated aqueous solution of sodium hydrogencarbonate anddichloromethane were added to the residue to conduct liquid separation.The resultant water layer was extracted with dichloromethane. Theresultant organic layers were collected and dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, and theresidue was purified by flash column chromatography on silica gel(dichloromethane:methanol=97:3→19:1) to obtain Stereoisomer A (585 mg)and Stereoisomer B (1.31 g). Each stereoisomer was dissolved inmethanol, and a 1N ethanol solution of hydrochloric acid was addedthereto. After the solvent was distilled off under reduced pressure,ethyl acetate was added to the residue. Precipitate formed was collectedby filtration to obtain the title compounds [Stereoisomer A (573 mg) andStereoisomer B (1.26 g)] as pale yellow solids.

[1178] Hydrochloride of Stereoisomer A:

[1179]¹H-NMR (DMSO-d₆) δ: 1.91-2.02(2H,m), 2.23-2.27(2H,m), 2.90(3H,s),3.06-3.14(3H,m), 3.46-3.64(5H,m), 4.38-4.64(4H,m), 7.10(1H,d,J=1.5 Hz),7.16(1H,dd,J=8.7,2.0 Hz), 7.39(1H,d,J=8,7 Hz), 7.70(1H,d,J=2.0 Hz),8.64(1H,d,J=8.3 Hz), 9.02(1H,d,J=8.6 Hz), 11.41(1H,br.s),11.79(1H,br.s). MS (FAB) m/z: 516(M+H)⁺.

[1180] Hydrochloride of Stereoisomer B:

[1181]¹H-NMR (DMSO-d₆) δ: 1.91-2.02(2H,m), 2.19-2.33(2H,m), 2.90(3H,s),3.05-3.17(3H,m), 3.46-3.68(5H,m), 4.39-4.64(4H,m), 7.11(1H,d,J=1.5 Hz),7.15(1H,dd,J=8.8,2.0 Hz), 7.38(1H,d,J=8,8 Hz), 7.70(1H,d,J=2.0 Hz),8.63(1H,d,J=8.6 Hz), 9.01(1H,d,J=8.8 Hz), 11.42(1H,br.s),11.78(1H,br.s). MS (FAB) m/z: 516(M+H)⁺.

Example 57 (1R*,2R*)-4-Carboxy-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediamine(Stereoisomer B)

[1182]

[1183] Stereoisomer B (900 mg) obtained in Example 56 was dissolved inmethanol (10 ml) and water (3 ml), and lithium hydroxide (84 mg) wasadded to stir the mixture at room temperature for 3 hours. The reactionmixture was neutralized, the solvent was concentrated under reducedpressure, and water was added to the residue. Insoluble matter wascollected by filtration to obtain the title compound (1.03 g) as a crudepale yellow solid.

[1184]¹H-NMR (DMSO-d₆) δ: 1.86-1.99(2H,m), 2.20-2.30(2H,m), 2.38(3H,s),2.76(2H,br.s), 2.84(2H,br.s), 2.95-3.03(1H,m), 3.66(2H,br.s),4.37-4.42(1H,m), 4.56-4.60(1H,m), 7.11(1H,s), 7.16(1H,d,J=8.5 Hz),7.40(1H,d,J=8,5 Hz), 7.70(1H,s), 8.58(1H,d,J=8.1 Hz), 8.81(1H,d,J=8.3Hz), 11.73(1H,br.s). MS (FAB) m/z: 502(M+H)⁺.

Example 58(1R*,2R*)-N¹-[(5-Chloroindol-2-yl)carbonyl]-4-(N-methylcarbamoyl)-N²-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride (Stereoisomer B)

[1185]

[1186] Stereoisomer B (195 mg) obtained in Example 57 was dissolved inN,N-dimethylformamide (5 ml), and 1-hydroxybenzotriazole monohydrate (26mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (149mg), methylamine hydrochloride (52 mg) and triethylamine (107 μl) wereadded to stir the mixture at room temperature for 24 hours. The solventwas distilled off under reduced pressure, and a saturated aqueoussolution of sodium hydrogencarbonate was added to the residue to conductextraction with dichloromethane. The resultant organic layer was driedover anhydrous sodium sulfate, and the solvent was then distilled offunder reduced pressure. The residue was purified by flash columnchromatography on silica gel (dichloromethane:methanol=9:1). Thethus-obtained pale yellow solid was dissolved in methanol, a 1N ethanolsolution (276 μl) of hydrochloric acid was added, the solvent wasconcentrated under reduced pressure, and ethyl acetate was added to theresidue. Precipitate formed was collected by filtration to obtain thetitle compound (140 mg) as a pale yellow solid.

[1187]¹H-NMR (DMSO-d₆) δ: 1.83-1.91(2H,m), 2.09-2.19(2H,m),2.59,2.60(3H,each s), 2.82-2.90(4H,m), 3.15(2H,br.s),3.44-3.67(2H,br.s), 4.34-4.63(4H,m), 7.12(1H,d,J=1.2 Hz),7.16(1H,dd,J=8.8,2.1 Hz), 7.39(1H,d,J=8,8 Hz), 7.69(1H,d,J=2.1 Hz),7.88,7.89(1H,each s), 8.81(1H,d,J=8.6 Hz), 8.97(1H,d,J=8.6 Hz),11.37(1H,br.s), 11.76(1H,br.s). MS (ESI) m/z: 515(M+H)⁺.

Example 59(1R*,2R*)-N¹-[(5-Chloroindol-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-N²-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride (Stereoisomer B)

[1188]

[1189] The title compound was obtained from Stereoisomer B obtained inExample 57 in a similar manner to Example 58.

[1190]¹H-NMR (DMSO-d₆) δ: 1.84-1.95(2H,m), 2.12-2.22(2H,m), 2.85(3H,s),2.88(3H,s), 3.01(3H,s), 3.05-3.10(1H,m), 3.15(2H,br.s), 3.29-3.53(2H,m),4.34-4.63(4H,m), 7.11(1H,s), 7.15(1H,dd,J=8.7,1.7 Hz), 7.38(1H,d,J=8.7Hz), 7.69(1H,d,J=1.7 Hz), 8.64(1H,d,J=8.6 Hz), 8.97(1H,d,J=8.8 Hz),11.39(1H,br.s), 11.76(1H,s). MS (ESI) m/z: 529(M+H)⁺.

Example 60(1R*,2R*)-4-Methoxy-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride (Stereoisomer A and Stereoisomer B)

[1191]

[1192] 1) (1R*,2R*)-4-Methoxy-1,2-cyclopentanediamine hydrochloride (470mg) was suspended in N,N-dimethylformamide (5 ml), and triethylamine(0.966 ml) and p-nitrophenyl 5-chloroindole-2-carboxylate (805 mg) wereadded to stir the mixture at room temperature for 4 days. The solventwas distilled off under reduced pressure, and a saturated aqueoussolution of sodium hydrogencarbonate and dichloromethane were added tothe residue to conduct liquid separation. The resultant organic layerswas dried over anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure, and the residue was purified by columnchromatography on silica gel (methanol:dichloromethane=1:9) to obtain(1R*,2R*)-4-methoxy-N¹-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclopentanediamine (mixture of stereoisomers at4-position) (268 mg) as yellow powder.

[1193] 2) A mixture of stereoisomers A and B of the title compound wassynthesized from the product (268 mg) obtained above in a similar mannerto Example 2, and the isomers were isolated by column chromatography onsilica gel in the same manner as in Example 56 and then converted intohydrochlorides to obtain the title compounds [Stereoisomer A (75 mg) andStereoisomer B (70 mg)].

[1194] Stereoisomer A:

[1195]¹H-NMR (DMSO-d₆) δ: 1.70-2.15(4H,m), 2.90(3H,s), 3.00-3.90(8H,m),4.10-4.80(4H,m), 7.08(1H,s), 7.16(1H,d,J=8.8 Hz), 7.38(1H,d,J=8.8 Hz),7.69(1H,s), 8.56(1H,d,J=8.8 Hz), 8.88(1H,d,J=8.3 Hz), 10.96(1H,br.s),11.75(1H,br.s) MS (FAB) m/z: 488(M+H)⁺.

[1196] Stereoisomer B:

[1197]¹H-NMR (DMSO-d₆) δ: 1.60-2.10(4H,m), 2.89(3H,s), 3.00-3.70(7H,m),3.70-3.90(1H,m), 4.20-4.80(4H,m), 7.05-7.20(2H,m), 7.38(1H,d,J=8.8 Hz),7.68(1H,s), 8.59(1H,d,J=8.3 Hz), 8.90(1H,d,J=8.5 Hz), 11.26(1H,br.s),11.74(1H,br.s). MS (FAB) m/z: 488(M+H)⁺.

Example 61(1R*,2R*)-4-Benzyloxy-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediamine(Stereoisomer A and Stereoisomer B)

[1198]

[1199] Stereoisomers A and B of the title compound were obtained from amixture of (1R*,2R*,4R*)- and(1R*,2R*,4S*)-4-benzyloxy-N¹-[(5-chloroindol-2-yl)-carbonyl]-1,2-cyclopentanediamines,and they were respectively isolated by column chromatography on silicagel to obtain the title compounds, Stereoisomers A and B.

[1200] Stereoisomer A:

[1201]¹H-NMR (CDCl₃) δ: 1.75-1.95(2H,m), 2.50(3H,s), 2.60-2.70(1H,m),2.70-2.90(5H,m), 3.65(1H,d,J=15.4 Hz), 3.74(1H,d,J=15.6 Hz),4.10-4.20(1H,m), 4.30-4.45(2H,m), 4.47(1H,d,J=11.7 Hz), 4.58(1H,d,J=12.0Hz), 6.88(1H,d,J=2.2 Hz), 7.20(1H,d.d,J=8.6 and 2.0 Hz),7.30-7.40(6H,m), 7.50(1H,d,J=5.4 Hz), 7.58(1H,d,J=7.3 Hz),7.63(1H,d,J=2.0 Hz), 9.19(1H,br.s). MS (FAB) m/z: 564(M+H)⁺.

[1202] Stereoisomer B:

[1203]¹H-NMR (CDCl₃) δ: 1.80-2.00(2H,m), 2.45-2.55(1H,m), 2.49(3H,s),2.70-2.90(5H,m), 3.65(1H,d,J=15.8 Hz), 3.72(1H,d,J=15.2 Hz),4.15-4.30(2H,m), 4.48(1H,d,J=11.3 Hz), 4.52(1H,d,J=11.5 Hz),4.55-4.70(1H,m), 6.68(1H,d,J=1.7 Hz), 7.18(1H,d.d,J=8.7 and 2.0 Hz),7.20-7.35(6H,m), 7.42(1H,d,J=7.8 Hz), 7.56(1H,d,J=1.7 Hz),7.60(1H,d,J=6.4 Hz), 9.31(1H,br.s). MS (FAB) m/z: 564(M+H)⁺.

Example 62(1R*,2R*)-N¹-[(5-Chloroindol-2-yl)carbonyl]-4-hydroxy-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediamine(Stereoisomer B) hydrochloride

[1204]

[1205] Dimethyl sulfide (8 ml) and anhydrous aluminum chloride (2.0 g)were dissolved in dichloromethane (100 ml), and Stereoisomer B (1.20 g)obtained in Example 61 was added to stir the mixture at room temperaturefor 8.5 hours. The reaction mixture was concentrated under reducedpressure, and diluted hydrochloric acid was added to the residue toacidify it. This solution was alkalified with a saturated aqueoussolution of sodium hydrogencarbonate and extracted with dichloromethane.The extract was dried over anhydrous magnesium sulfate, and the solventwas then distilled off under reduced pressure. The residue was purifiedby column chromatography on silica gel (dichloromethane:methanol=9:1) toobtain yellow powder (0.93 g). A 1N ethanol solution of hydrochloricacid was added to this powder (100 mg) into a solution, and the solutionwas concentrated under reduced pressure to obtain the title compound (84mg) as pale yellow powder.

[1206]¹H-NMR (DMSO-d₆) δ: 1.55-1.70(1H,m), 1.85-1.95(2H,m),2.25-2.35(1H,m), 2.93(3H,s), 3.00-3.20(2H,m), 3.35-3.70(2H,m),4.15-4.25(1H,m), 4.30-4.75(3H,m), 7.13(1H,d,J=2.2 Hz), 7.15(1H,d.d,J=8.8and 2.2 Hz), 7.38(1H,d,J=9.3 Hz), 7.67(1H,s), 8.57(1H,d,J=8.1 Hz),8.88(1H,d,J=8.3 Hz), 10.79(1H,br.s), 11.72(1H,s). MS (FAB) m/z:474(M+H)⁺.

Example 63(1R*,2R*)-4-Acetoxy-N¹-(5-chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediamine(Stereoisomer B)

[1207]

[1208] Stereoisomer B (208 mg) obtained in Example 62 was dissolved inpyridine (3 ml), and acetyl chloride (35.5 μl ) was added at roomtemperature to stir the mixture for 3.5 hours. The reaction mixture wasconcentrated under reduced pressure, and the residue was alkalified witha saturated aqueous solution of sodium hydrogencarbonate and extractedwith dichloromethane. The extract was dried over anhydrous magnesiumsulfate, and the solvent was then distilled off under reduced pressure.The residue was purified by column chromatography on silica gel(dichloromethane hexane=1:1) to obtain the title compound (180 mg) aspowder.

[1209]¹H-NMR (CDCl₃) δ: 1.70-1.85(1H,m), 2.00-2.15(1H,m), 2.06(3H,s),2.20-2.35(1H,m), 2.50(3H,s), 2.70-3.10(5H,m), 3.66(1H,d,J=15.1 Hz),3.73(1H,d,J=15.4 Hz), 4.05-4.20(1H,m), 4.60-4.75(1H,m), 5.15-5.30(1H,m),6.90(1H,d,J=1.2 Hz), 7.21(1H,d.d,J=8.8 and 2.0 Hz), 7.31(1H,d,J=8.5 Hz),7.48(1H,d,J=7.8 Hz), 7.63(1H,d,J=2.0 Hz), 7.67(1H,d,J=5.4 Hz),9.30(1H,br.s). MS (FAB) m/z: 516(M+H)⁺.

Example 64(1R*,2R*)-N¹-[(5-Chloroindol-2-yl)carbonyl]-4-hydroxymethyl-N²-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride (Stereoisomer A)

[1210]

[1211] 1)(1R*,2R*)-4-Benzyloxymethyl-N¹-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclopentanediamine(794 mg) was dissolved in N,N-dimethylformamide (150 ml), and lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate (694mg), 1-hydroxybenzotriazole monohydrate (61 mg) and1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (1.15 g)were added to stir the mixture overnight at room temperature. Thereaction mixture was concentrated under reduced pressure, and water wasadded to the residue to conduct extraction with dichloromethane. Theresultant organic layer was dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure, and the residue waspurified by preparative thin-layer chromatography (dichloromethaneacetone=2:1) to obtain Stereoisomer A (378 mg) and Stereoisomer B (354mg) of(1R*,2R*)-4-benzyloxymethyl-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediamine.

[1212] Stereoisomer A:

[1213]¹H-NMR (CDCl₃) δ: 1.50-1.53(1H,m), 1.76-1.84(1H,m),2.31-2.40(2H,m), 2.49(3H,s), 2.51-2.59(1H,m), 2.72-2.93(4H,m),3.38-3.50(2H,m), 3.66(1H,d,J=15.4 Hz), 3.73(1H,d,J=15.4 Hz),4.10-4.19(1H,m), 4.38-4.47(1H,m), 4.55(2H,s), 6.88(1H,s),7.20(1H,dd,J=8.8,1.5 Hz), 7.25-7.37(6H,m), 7.55(1H,d,J=6.3 Hz),7.64(1H,s), 9.16(1H,s). MS (FAB) m/z: 578(M+H)⁺.

[1214] Stereoisomer B:

[1215]¹H-NMR (CDCl₃) δ: 1.40-1.51(1H,m), 1.83-1.92(1H,m),2.10-2.18(1H,m), 2.49(3H,s), 2.51-2.68(2H,m), 2.73-2.94(4H,m),3.39-3.49(2H,m), 3.63(1H,d,J=15.4 Hz), 3.72(1H,d,J=15.4 Hz),4.14-4.23(1H,m), 4.41-4.50(2H,m), 4.54(2H,s), 6.72(1H,d,J=1.7 Hz),7.17(1H,dd,J=8.8,2.0 Hz), 7.27-7.42(6H,m), 7.57(1H,d,J=1.7 Hz),7.66(1H,d,J=6.1 Hz), 9.41(1H,s). MS (FAB) m/z: 578(M+H)⁺.

[1216] 2) The benzyl group of the above Stereoisomer A was eliminated inthe same manner as in Example 62 to obtain the title compound (269 mg).

[1217]¹H-NMR (DMSO-d₆) δ: 1.41-1.52(1H,m), 1.69-1.90(2H,m),2.03-2.30(2H,m), 2.90(3H,s), 3.09-3.19(2H,m), 3.40-3.73(5H,m),4.40-4.74(4H,m), 7.11(1H,s), 7.15(1H,dd,J=8.6,2.0 Hz), 7.38(1H,d,J=8.6Hz), 7.69(1H,J=1.7 Hz), 8.52(1H,J=8.6 Hz), 8.88(1H,J=8.6 Hz),11.07(1H,br.s), 11.74(1H,s). MS (FAB) m/z: 488(M+H)⁺.

Example 65(1R*,2R*)-N¹-[(5-Chloroindol-2-yl)carbonyl]-4-hydroxymethyl-N²-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride (Stereoisomer B)

[1218]

[1219] The title compound was obtained from Stereoisomer B obtainedin 1) of Example 64 in a similar manner to 2) of Example 64.

[1220]¹H-NMR (DMSO-d₆) δ: 1.35-1.40(1H,m), 1.78-1.90(2H,m),2.01-2.11(1H,m), 2.19-2.30(1H,m), 2.91(3H,s), 3.10-3.77(7H,m),4.27-4.78(4H,m), 7.09(1H,s), 7.15(1H,d,J=8.8 Hz), 7.38(1H,d,J=8.8 Hz),7.69(1H,s), 8.52(1H,d,J=8.3 Hz), 8.90(1H,d,J=8.3 Hz.), 10.97(1H,br.s),11.73(1H,s). MS (FAB) m/z: 488(M+H)⁺.

Example 66 Isolation of Optically Active Compound of(1R*,2R*)-N¹-[(5-chloroindol-2-yl)carbonyl]-4-hydroxymethyl-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediamine(Stereoisomer A)

[1221] Stereoisomer A obtained in Example 64 was divided into opticallyactive compound by HPLC (hexane:isopropylalcohol:diethylamine=80:20:0.5; flow rate 12 ml/min) making use ofCHIRALPAK AD (Daicel Chemical Industries, Ltd.) to obtain OpticallyActive Compound A1 eluted in 45 minutes and Optically Active Compound A2eluted in 62 minutes. After 1N hydrochloric acid (1 ml) was added to therespective optically active compounds to suspend them, each suspensionwas concentrated under reduced pressure to obtain the hydrochloride (92mg) of Optically Active Compound A1 and the hydrochloride (74 mg) ofOptically Active Compound A2 as pale brown foamy substances.

[1222] Hydrochloride of Optically Active Compound A1:

[1223]¹H-NMR (DMSO-d₆) δ: 1.41-1.52(1H,m), 1.69-1.90(2H,m),2.03-2.30(2H,m), 2.90(3H,s), 3.09-3.19(2H,m), 3.40-3.73(5H,m),4.40-4.74(4H,m), 7.11(1H,s), 7.15(1H,dd,J=8.6,2.0 Hz), 7.38(1H,d,J=8.6Hz), 7.69(1H,J=1.7 Hz), 8.52(1H,J=8.6 Hz), 8.88(1H,J=8.6 Hz),11.07(1H,br.s), 11.74(1H,s). MS (FAB) m/z: 488(M+H)⁺.

[1224] Hydrochloride of Optically Active Compound A2:

[1225]¹H-NMR (DMSO-d₆) δ: 1.41-1.52(1H,m), 1.69-1.90(2H,m),2.03-2.30(2H,m), 2.90(3H,s), 3.09-3.19(2H,m), 3.40-3.73(5H,m),4.40-4.74(4H,m), 7.11(1H,s), 7.15(1H,dd,J=8.6,2.0 Hz), 7.38(1H,d,J=8.6Hz), 7.69(1H,J=1.7 Hz), 8.52(1H,J=8.6 Hz), 8.88(1H,J=8.6 Hz),11.07(1H,br.s), 11.74(1H,s). MS (FAB) m/z: 488(M+H)⁺.

Example 67(1R*,2R*)-N¹-[(5-Chloroindol-2-yl)carbonyl]-4-hydroxymethyl-N²-[(5-isopropyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride (Stereoisomer A)

[1226]

[1227] 1) Stereoisomers A and B of(1R*,2R*)-4-benzyloxymethyl-N¹-[(5-chloroindol-2-yl)carbonyl]-4-hydroxymethyl-N²-[(5-isopropyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminewere obtained from(1R*,2R*)-4-benzyloxymethyl-N¹-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclopentanediamineand lithium5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2-carboxylatein a similar manner to 1) of Example 64.

[1228] Stereoisomer A:

[1229]¹H-NMR (CDCl₃) δ: 1.12(6H,d,J=6.4 Hz), 1.53-1.63(1H,m),1.75-1.85(1H,m), 2.29-2.39(2H,m), 2.47-2.58(1H,m), 2.78-3.02(5H,m),3.37-3.49(2H,m), 3.76(1H,d,J=15.1 Hz), 3.83(1H,d,J=15.1 Hz),4.15-4.23(1H,m), 4.40-4.50(1H,m), 4.54(2H,s), 6.88(1H,d,J=1.7 Hz),7.16(1H,dd,J=8.8,2.0 Hz), 7.27-7.38(6H,m), 7.58(1H,d,J=7.3 Hz),7.60(1H,s), 7.64(1H,d,J=5.6 Hz), 9.56(1H,s). MS (FAB) m/z: 606(M+H)⁺.

[1230] Stereoisomer B:

[1231]¹H-NMR (CDCl₃) δ: 1.12(1H,d,J=6.6 Hz), 1.42-1.52(1H,m),1.82-1.92(1H,m), 2.10-2.20(1H,m), 2.48-2.68(2H,m), 2.80-3.02(5H,m),3.40-3.49(2H,m), 3.77(1H,d,J=15.5 Hz), 3.83(1H,d,J=15.5 Hz),4.15-4.25(1H,m), 4.42-4.52(1H,m), 4.53(1H,d,J=1.0 Hz), 6.74(1H,d,J=1.5Hz), 7.17(1H,dd,J=8.8,2.0 Hz), 7.27-7.37(6H,m), 7.41(1H,d,J=7.8 Hz),7.57(1H,d,J=2.0 Hz), 7.68(1H,d,J=6.1 Hz), 9.51(1H,s). MS (FAB) m/z:606(M+H)⁺.

[1232] 2) The title compound was obtained from the above Stereoisomer Ain a similar manner to 2) of Example 64.

[1233]¹H-NMR (DMSO-d₆) δ: 1.30-1.40(6H,m), 1.43-1.53(1H,m),1.71-1.91(2H,m), 2.09-2.16(1H,m), 2.19-2.31(1H,m), 3.04-3.15(1H,m),3.34-3.77(7H,m), 4.30-4.67(4H,m), 7.12(1H,s), 7.16(1H,d,J=8.8 Hz),7.40(1H,d,J=8.8 Hz), 7.69(1H,s), 8.56(1H,d,J=8.3 Hz), 8.85(1H,d,J=8.3Hz), 11.42(1H,br.s), 11.77(0.5H,s),11.80(0.5H,s). MS (FAB) m/z:516(M+H)⁺.

Example 68(1R*,2R*)-N¹-[(5-Chloroindol-2-yl)carbonyl]-4-hydroxymethyl-N²-[(5-isopropyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride (Stereoisomer B)

[1234]

[1235] The title compound was obtained from the Stereoisomer B obtainedin 1) of Example 67 in a similar manner to 2) of Example 67.

[1236]¹H-NMR (DMSO-d₆) δ: 1.30-1.39(6H,m), 1.40-1.54(1H,m),1.75-1.90(2H,m), 2.02-2.11(1H,m), 2.18-2.30(1H,m), 3.05-3.15(1H,m),3.30-3.55(5H,m), 3.60-3.79(2H,m), 4.29-4.38(1H,m), 4.41-4.67(3H,m),7.10(1H,s), 7.15(1H,d,J=8.8 Hz), 7.39(1H,d,J=8.8 Hz), 7.69(1H,s),8.54(1H,d,J=8.5 Hz), 8.87(1H,d,J=8.5 Hz), 11.29(1H,br.s), 11.75(0.5H,s),11.78(0.5H,s). MS (FAB) m/z: 516(M+H)⁺.

Example 69(1R*,2R*)-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[[5-(1,1-dimethyl-2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-4-hydroxymethyl-1,2-cyclopentanediaminehydrochloride (Stereoisomer A)

[1237]

[1238] 1) Stereoisomers A and B of(1R*,2R*)-4-benzyloxymethyl-N¹-[[5-[2-(tert-butyldiphenylsilyloxy)-1,1-dimethylethyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl]carbonyl]-N²-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclopentanediaminewere obtained from(1R*,2R*)-4-benzyloxymethyl-N¹-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclopentanediamineand lithium5-[2-(tert-butyldiphenylsilyloxy)-1,1-dimethylethyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2-carboxylatein a similar manner to Example 2.

[1239] Stereoisomer A:

[1240]¹H-NMR (CDCl₃) δ: 1.05(9H,s), 1.168, 1.171(6H,each s),1.53-1.61(1H,m), 1.76-1.88(1H,m), 2.30-2.37(2H,m), 2.78-2.79(2H,m),2.87-2.90(1H,m), 2.96-3.00(1H,m), 3.37-3.47(2H,m), 3.58(2H,s),3.96(1H,q,J=13.1 Hz), 4.41-4.45(1H,m), 4.51-4.57(2H,m), 6.88(1H,d,J=1.5Hz), 7.17(1H,dd,J=8.8,2.0 Hz), 7.23-7.43(12H,m), 7.52(1H,d,J=7.6 Hz),9.37(1H,br.s).

[1241] Stereoisomer B:

[1242]¹H-NMR (CDCl₃) δ: 1.05(9H,s), 1.17(6H,s), 1.43-1.47(1H,m),1.85-1.88(1H,m), 2.09-2.14(1H,m), 2.58-2.63(1H,m), 2.78-2.79(2H,m),2.86-2.90(1H,m), 2.96-3.00(1H,m), 3.38-3.46(2H,m), 3.59(2H,s),3.95(1H,q,J=13.3 Hz), 4.15-4.20(1H,m), 4.45-4.56(3H,m), 6.74(1H,d,J=2.0Hz), 7.16(1H,dd,J=8.8,2.0 Hz), 7.27-7.43(12H,m), 7.57(1H,d,J=2.0 Hz),9.48(1H,br.s).

[1243] 2) The above Stereoisomer A (288 mg) was suspended indichloromethane (20 ml), and dimethyl sulfide (1.15 ml) and anhydrousaluminum chloride (350 mg) were added to stir the mixture at roomtemperature for 1 hour. A 1N aqueous solution (10 ml) of sodiumhydroxide was added to the reaction mixture, and the mixture wasextracted with dichloromethane. The resultant organic layer was driedover anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by flash columnchromatography on silica gel (dichloromethane:methanol=9:1) to obtain(1R*,2R*)-N¹-[[5-[2-(tert-butyldiphenylsilyloxy)-1,1-dimethylethyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-N²-[(5-chloroindol-2-yl)carbonyl]-4-hydroxymethyl-1,2-cyclopentanediamine(Stereoisomer A) (184 mg) as a pale yellow solid.

[1244]¹H-NMR (CDCl₃) δ: 1.04(9H,s), 1.15(6H,s), 1.54-1.62(1H,m),1.73-1.81(1H,m), 1.99-2.25(2H,m), 2.34-2.38(2H,m), 2.67-2.85(3H,m),2.92-2.97(1H,m), 3.48-3.62(4H,m), 3.93(1H,q,J=15.6 Hz), 4.20-4.28(1H,m),4.47-4.56(1H,m), 6.89(1H,s), 7.11-7.18(1H,m), 7.24-7.27(1H,m),7.32-7.43(6H,m), 7.54(1H,d,J=1.7 Hz), 7.63(4H,dd,J=7.8,1.5 Hz),7.90-7.92(2H,m), 10.13(1H,br.s). MS (FAB) m/z: 784(M+H)⁺.

[1245] 3) Stereoisomer A (180 mg) obtained in the step 2) describedabove was dissolved in a 1N tetrahydrofuran solution (2 ml) oftetrabutylammonium fluoride, and the solution was stirred overnight atroom temperature. Dichloromethane, a 1N aqueous solution of sodiumhydroxide and sodium chloride were added to the reaction mixture toconduct liquid separation. The resultant organic layer was dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, and the residue was purified by flash column chromatography onsilica gel (dichloromethane:methanol=19:1). The thus-obtained powder wasdissolved in methanol, and a 1N ethanol solution (229 μl) ofhydrochloric acid was added, to which ethyl acetate was added. Thesolvent was concentrated under reduced pressure to obtain the titlecompound (63 mg) as a pale brown solid.

[1246]¹H-NMR (DMSO-d₆) δ: 1.33-1.50(8H,m), 1.70-1.91(2H,m),2.07-2.14(1H,m), 2.23-2.24(1H,m), 3.04-3.10(1H,m), 3.27-3.44(4H,m),3.57-3.70(2H,m), 3.92-3.95(1H,m), 4.29-4.72(4H,m), 5.81(1H,br.s),7.11(1H,s), 7.15(1H,dd,J=8.6,2.0 Hz), 7.39(1H,d,J=8.6 Hz),7.68(1H,d,J=2.0 Hz), 8.53-8.56(1H,m), 8.83(1H,d,J=8.3 Hz),10.36(1H,br.s), 11.75,11.77(1H,each s). MS (ESI) m/z: 546(M+H)⁺.

Example 70(1R*,2R*)-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[[5-(1-dimethyl-2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-4-hydroxymethyl-1,2-cyclopentanediaminehydrochloride (Stereoisomer B)

[1247]

[1248] The title compound was obtained by eliminating the benzyl groupof (1R*,2R*)-4-benzyloxymethyl-N¹-[(5-chloroindol-2-yl)carbonyl]-N2-[5-[2-(tert-butyldiphenylsilyl)oxy-1,1-dimethylethyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediamine(Stereoisomer B) obtained in 1) of Example 69 and then eliminating thetert-butyldiphenylsilyl group in the same manner as in 3) of Example 69.

[1249]¹H-NMR (DMSO-d₆) δ: 1.32-1.46(8H,m), 1.78-1.91(2H,m),2.03-2.10(1H,m), 2.24(1H,m), 3.05-3.11(1H,m), 3.26-3.37(3H,m),3.58-3.69(2H,m), 3.92(1H,br.s), 4.29-4.36(1H,m), 4.52-4.72(4H,m),5.80-5.81(1H,m), 7.10(1H,s), 7.15(1H,d,J=8.8 Hz), 7.39(1H,d,J=8.8 Hz),7.69(1H,s), 8.53(1H,d,J=7.6 Hz), 8.86(1H,d,J=8.1 Hz), 10.28(1H,br.s),11.75,11.76(1H,each s). MS (ESI) m/z: 546(M+H)⁺.

Example 71(1R*,2R*)-4-Carbamoyloxymethyl-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediamine(Stereoisomer A)

[1250]

[1251](1R*,2R*)-N¹-[(5-Chloroindol-2-yl)carbonyl]-4-hydroxymethyl-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediamine(Stereoisomer A) (200 mg) was suspended in tetrahydrofuran (80 ml), andpyridine (100 μl) was added, and phenyl chloroformate (156 μl) was thenadded to stir the mixture at room temperature for 10 minutes. Asaturated methanol solution (10 ml) of ammonia was added to the reactionmixture, and the mixture was left to stand overnight at roomtemperature. The reaction mixture was concentrated under reducedpressure, and a 1:9 mixed solvent (100 ml) of methanol anddichloromethane and a 1N aqueous solution (50 ml) of sodium hydroxidewere added to the residue to conduct liquid separation. The resultantorganic layer was then dried over anhydrous sodium sulfate. The solventwas distilled off under reduced pressure, and the residue was purifiedby column chromatography on silica gel (dichloromethane:methanol=10:1).The thus-obtained colorless amorphous solid was suspended in 1Nhydrochloric acid (1 ml), and the suspension was concentrated underreduced pressure to obtain the title compound (151 mg) as a pale yellowsolid.

[1252]¹H-NMR (DMSO-d₆) δ: 1.44-1.56(1H,m), 1.70-1.90(2H,m),2.05-2.15(1H,m), 2.35-2.45(1H,m), 3.02-3.26(2H,m), 3.39-3.72(2H,m),3.80-3.92(2H,m), 4.30-4.42(2H,m), 4.49-4.59(1H,m), 4.60-4.70(1H,m),6.46(2H,br.s), 7.10(1H,s), 7.14(1H,dd,J=8.8,2.0 Hz), 7.38(1H,d,J=8.8Hz), 7.68(1H,s), 8.57(1H,J=8.3 Hz), 8.91(1H,J=8.3 Hz), 11.48(1H,br.s),11.75(1H,s). MS (FAB) m/z: 531(M+H)⁺.

Example 72(1R*,2R*)-N¹-[(5-Chloroindol-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)oxymethyl-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediamine(Stereoisomer A)

[1253]

[1254] The title compound was obtained from(1R*,2R*)-N¹-[(5-chloroindol-2-yl)carbonyl]-4-hydroxymethyl-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediamine(Stereoisomer A) in a similar manner to Example 71.

[1255]¹H-NMR (DMSO-d₆) δ: 1.50-1.60(1H,m), 1.76-1.90(2H,m),2.06-2.15(1H,m), 2.39-2.46(1H,m), 2.75-2.93(9H,m), 3.14(2H,br.s),3.38-3.73(2H,m), 3.89-3.90(1H,m), 4.28-4.71(4H,m), 7.09(1H,s),7.15(1H,dd,J=8.6,2.0 Hz), 7.37(1H,d,J=8.6 Hz), 7.68(1H,s),8.57(1H,d,J=8.3 Hz), 8.94(1H,d,J=8.3 Hz), 11.42(1H,br.s), 11.74(1H,s).MS (FAB) m/z: 559(M+H)⁺.

Example 73 (1R*,2R*)-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-morpholinocarbonyloxymethyl-1,2-cyclopentanediamine(Stereoisomer B)

[1256]

[1257] The title compound was obtained from (1R*,2R*)-N¹-[(5-chloroindol-2-yl)carbonyl]-4-hydroxymethyl-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediamine(Stereoisomer B) in a similar manner to Example 71.

[1258]¹H-NMR (DMSO-d₆) δ: 1.43-1.52(1H,m), 1.80-1.90(2H,m),2.07-2.17(2H,m), 2.85(3H,s), 3.12(2H,br.s), 3.25-3.65(1OH,m),3.91-4.04(2H,m), 4.32-4.65(6H,m), 7.08(1H,s), 7.14(1H,d,J=8.8 Hz),7.37(1H,d,J=8.8 Hz), 7.68(1H,s), 8.54(1H,d,J=8.6 Hz), 8.93(1H,d,J=8.6Hz), 11.40(1H,br.s), 11.75(1H,s). MS (FAB) m/z: 601(M+H)⁺.

Example 74(±)-trans-4,4-Bis(methoxymethyl)-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(5-isopropyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminehydrochloride

[1259]

[1260] The title compound (300 mg) was obtained as a pale yellow foamysubstance by dissolving(±)-trans-4,4-bis(methoxymethyl)-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclopentanediamine(365 mg), lithium5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carboxylate(395 mg) and 1-hydroxybenzotriazole monohydrate (31 mg) inN,N-dimethylformamide (50 ml) and causing1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (575 mg) toreact as a condensing agent in a similar manner to Example 2.

[1261]¹H-NMR (DMSO-d₆) δ: 1.33(6H,br.s), 1.59-1.72(1H,m),1.80-1.95(1H,m), 3.01-3.14(1H,m), 3.18-3.45(12H,m), 3.60-3.80(2H,m),4.30-4.69(4H,m), 7.11(1H,s), 7.15(1H,dd,J=8.5,2.0 Hz), 7.39(1H,d,J=8.5Hz), 7.69(1H,d,J=2.0 Hz), 8.49(1H,d,J=8.3 Hz), 8.80(1H,d,J=8.3 Hz),11.11(1H,br.s), 11.69-11.80(1H,m). MS (FAB) m/z: 574(M+H)⁺.

Example 75(±)-trans-4,4-Bis(hydroxymethyl)-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(5-isopropyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediamine

[1262]

[1263] 1)(±)-trans-4,4-Bis(benzyloxymethyl)-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediaminewas obtained from(±)-trans-4,4-bis(benzyloxymethyl)-N¹-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclopentanediamineand lithium5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carboxylate ina similar manner to Example 2.

[1264]¹H-NMR (DMSO-d₆) δ: 1.01(6H,d,J=6.6 Hz), 1.60-1.72(2H,m),1.89-1.99(2H,m), 2.76(4H,br.s), 2.85-2.95(1H,m), 3.32-3.43(4H,m),3.69-3.74(2H,m), 4.32-4.44(1H,m), 4.48-4.60(5H,m), 7.07(1H,s),7.13(1H,dd,J=8.8,2.0 Hz), 7.23-7.40(11H,m), 7.67(1H,d,J=1.7 Hz),8.45(1H,d,J=8.6 Hz), 8.65(1H,d,J=8.6 Hz), 11.69(1H,s). MS (FAB) m/z:726(M+H)⁺.

[1265] 2) The title compound was obtained by eliminating the benzylgroup of the product obtained above in the same manner as in Example 62.

[1266]¹H-NMR (DMSO-d₆) δ: 1.22-1.39(6H,m), 1.44-1.60(2H,m),1.85-1.98(2H,m), 3.00-3.78(9H,m), 4.25-4.80(4H,m), 7.09(1H,s),7.14(1H,d,J=8.8 Hz), 7.37(1H,d,J=8.8 Hz), 7.67(1H,s), 8.48(1H,d,J=8.5Hz), 8.73(1H,d,J=8.5 Hz), 10.82(1H,br.s), 11.72(1H,s). MS (FAB) m/z:546(M+H)⁺.

Example 76(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(thiophen-2-yl)sulfonyl]-1,2-cyclohexanediamine

[1267]

[1268] (±)-cis-N-[(5-Chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride (200 mg) was dissolved in N,N-dimethylformamide (1 ml),and triethylamine (0.28 ml) and 2-thiophenesulfonyl chloride (111 mg)were added to stir the mixture for 75 minutes. Water was added to thereaction mixture, and deposit was collected by filtration andrecrystallized from methanol to obtain the title compound (198 mg) ascolorless crystals.

[1269]¹H-NMR (DMSO-d₆) δ: 1.20-1.80(8H,m), 3.52(1H,br.s), 3.97(1H,br.s),6.86(1H,t,J=4.5 Hz), 7.01(1H,s), 7.17(1H,dd,J=8.3,2.2 Hz),7.43(1H,d,J=8.6 Hz), 7.51(1H,s), 7.60-7.70(2H,m), 7.73(1H,s),7.80(1H,d,J=8.3 Hz), 11.71(1H,s) MS (FAB)m/z: 437(M+H)⁺.

Example 77(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-(2-butynoyl)-1,2-cyclohexanediamine

[1270]

[1271] The title compound was obtained from(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and tetrolic acid in a similar manner to Example 2.

[1272]¹H-NMR (CDCl₃) δ: 1.40-1.81(6H,m), 1.81-1.92(1H,m), 1.99(3H,s),2.08-2.17(1H,m), 4.11(1H,br.s), 4.29(1H,br.s), 6.22(1H,br,J=6.8 Hz),6.87(1H,d,J=2.0 Hz), 7.22(1H,dd,J=8.8,2.0 Hz), 7.34(1H,d,J=8.8 Hz),7.61(1H,s), 7.70(1H,br.s), 9.31(1H,s). MS (ESI)m/z: 358(M+H)⁺.

Example 78(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-phenylpropioloyl-1,2-cyclohexanediamine

[1273]

[1274] The title compound was obtained from(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and phenylptopiolic acid in a similar manner to Example 2.

[1275]¹H-NMR (CDCl₃) δ: 1.40-2.00(7H,m), 2.09-2.10(1H,m), 4.17(1H,br.s),4.36(1H,br.s), 6.45(1H,br,J=5.6 Hz), 6.90(1H,d,J=2.0 Hz), 7.10-73(9H,m),9.50(1H,s). MS (ESI) m/z: 420(M+H)⁺.

Example 79 (±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(pyridin-4-yl)carbonyl]-1,2-cyclohexanediamine hydrochloride

[1276]

[1277] The title compound was obtained from(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and isonicotinic acid in a similar manner to Example 2.

[1278]¹H-NMR (DMSO-d₆) δ: 1.04(2H,br.s), 1.62(2H,d,J=10.2 Hz),1.74(2H,br.s), 1.99(2H,d,J=4.6 Hz), 4.23-4.35(2H,m),7.16(2H,dd,J=8.8,1.8 Hz), 7.23(1H,s), 7.40(1H,d,J=8.8 Hz),7.63(1H,d,J=1.8 Hz), 8.25(2H,d,J=6.1 Hz), 8.33(1H,br,J=7.3 Hz),8.88(1H,br,J=6.6 Hz), 8.94(2H,d,J=6.1 Hz), 11.93(1H,s). MS (ESI)m/z:397(M+H)⁺.

Example 80(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-(4-dimethylaminobenzoyl)-1,2-cyclohexanediaminehydrochloride

[1279]

[1280] The title compound was obtained from(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and 4-dimethylaminobenzoic acid in a similar manner toExample 2.

[1281]¹H-NMR (DMSO-d₆) δ: 1.40(2H,br.s), 1.61(4H,br.s), 1.97(2H,br.s),2.96(6H,s), 4.13-4.25(2H,m), 6.88(2H,d,J=8.5 Hz), 7.16(1H,dd,J=8.8,2.0Hz), 7.17(1H,s), 7.40(1H,d,J=8.8 Hz), 7.65(1H,d,J=2.0 Hz),7.77(2H,d,J=8.5 Hz), 7.90(1H,br,J=6.8 Hz), 8.18(1H,br,J=6.8 Hz),l1.91(1H,s). MS (ESI)m/z: 439(M+H)⁺.

Example 81(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[3-(4-pyridyl)acryloyl]-1,2-cyclohexanediaminehydrochloride

[1282]

[1283] The title compound was obtained from(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and 3-(4-pyridyl)acrylic acid in a similar manner toExample 2.

[1284]¹H-NMR (DMSO-d₆)δ: 1.21(2H,br.s),1.50-1.67(3H,m),1.67-1.80(1H,m),1.80-1.96(2H,m),4.11-4.30(2H,m), 7.15(1H,dd,J=8.8,1.7Hz),7.21(1H,s),7.40(1H,d,J=8.8 Hz), 7.42(1H,d,J=16.0Hz),7.53(1H,d,J=16.0 Hz), 7.62(1H,d,J=1.7 Hz), 8.06(2H,d,J=6.0 Hz),8.27(1H,br,J=7.6 Hz), 8.50(1H,br,J=7.6 Hz), 8.87(2H,d,J=6.0 Hz),11.86(1H,s). MS (ESI) m/z:423(M+H)⁺.

Example 82(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(1-isopropylpiperidin-4-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1285]

[1286] The title compound was obtained from(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and lithium 1-isopropylpiperidine-4-carboxylate in asimilar manner to Example 2.

[1287]¹H-NMR (DMSO-d₆) δ: 0.94-2.10(1H,m), 1.22(6H,d,J=6.1 Hz),2.60-2.94(4H,m), 2.98-3.50(4H,m), 4.01(1H,br.s), 4.12(1H,br.s),7.16(1H,d,J=8.4 Hz), 7.20(1H,s), 7.42(1H,d,J=8.4 Hz),7.65(1H,s),7.93(1H,br,J=7.1 Hz), 8.17(1H,br,J=7.8 Hz), 9.59(1H,br.s),11.91(1H,s). MS (ESI)m/z: 445(M+H)⁺.

Example 83 (±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N-[[(E)-3-(1-methylpiperidin-4-yl)acryloyl]-1,2-cyclohexanediaminehydrochloride

[1288]

[1289] 1) Water (1 ml) and lithium hydride (10 mg) were added to asolution with1-(tert-butoxycarbonyl)-4-[(E)-2-(methoxycarbonyl)ethenyl]piperidine (J.Med. Chem., 1998, Vol. 41, p. 2492) (110 mg) dissolved intetrahydrofuran (4.0 ml) at room temperature, and the mixture wasstirred for 3 days. The reaction mixture was concentrated under reducedpressure, and the residue was dissolved in N,N-dimethylformamide (3 ml),to which(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexane-diaminehydrochloride (134 mg), 1-hydroxybenzotriazole monohydrate (111 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (157 mg) anddiisopropylethylamine (286 μl) were added at room temperature, and themixture was stirred for 7 days. The reaction mixture was concentratedunder reduced pressure, and dichloromethane (20 ml), water (50 ml) and asaturated aqueous solution (50 ml) of sodium hydrogencarbonate wereadded to the residue to separate an organic layer. The organic layer wasdried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by column chromatographyon silica gel (dichloromethane acetone=10:1→2:1) to obtain(±)-cis-N¹-[[(E)-3-[1-(tert-butoxycarbonyl)piperidin-4-yl]acryloyl]-N²-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine(215 mg) as a white solid.

[1290]¹H-NMR (CDCl₃) δ: 1.24-1.80(10H,m), 1.47(9H,s), 1.85-1.97(1H,m),2.10-2.20(1H,m), 2.22-2.36(1H,m), 2.68-2.74(2H,m), 4.12(3H,brs),4.29(1H,br.s), 5.84(1H,d,J=15.2 Hz), 6.06(1H,br.s), 6.89(1H,s),6.92(1H,dd,J=15.2,6.4 Hz), 7.23(1H,dd,J=8.8,1.7 Hz), 7.35(1H,d,J=8.8Hz), 7.64(1H,d,J=1.7 Hz), 8.04(1H,br.s), 9.41(1H,s). MS (ESI) m/z:529(M+H)⁺.

[1291] 2) Trifluoroacetic acid (1 ml) was added to a solution with theproduct (210 mg) obtained above dissolved in dichloromethane (1 ml) atroom temperature, and the mixture was stirred for 30 minutes. Thereaction mixture was concentrated under reduced pressure, and theresidue was dissolved in dichloromethane (5 ml), to which triethylamine(111 μl), acetic acid (68 μl), 35% formalin (51 μl ) and sodiumtriacetoxyborohydride (126 mg) were added at room temperature. Theresultant mixture was stirred for 4 hours. Dichloromethane (10 ml) andsaturated aqueous solution (10 ml) of sodium hydrogencarbonate wereadded to the reaction mixture to separate an organic layer. The organiclayer was dried over anhydrous sodium sulfate. The solvent was distilledoff under reduced pressure, and the residue was purified by reversedphase HPLC (aqueous solution of formic acid-acetonitrile system). Solidsthus obtained were dissolved in 1N hydrochloric acid-dichloromethanesystem, and the solution was concentrated to obtain the title compound(12 mg) as a white solid.

[1292]¹H-NMR (DMSO-d₆) δ: 1.30-1.93(12H,m), 2.25-2.38(1H,m),2.70(3H,d,J=4.9 Hz), 2.87-2.-3.00(2H,m), 3.34-3.44(2H,m), 4.13(2H,br.s),6.20(1H,d,J=15.5 Hz), 6.55(1H,dd,J=15.5,5.9 Hz), 7.18(1H,dd,J=8.8,2.1Hz), 7.20(1H,d,J=1.5 Hz), 7.43(1H,d,J=8.8 Hz), 7.67(1H,d,J=2.1 Hz),8.01(1H,br,J=7.6 Hz), 8.29(1H,br,J=7.1 Hz), 10.40(1H,br.s), 11.89(1H,s).MS (ESI) m/z: 443(M+H)⁺.

Example 84(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[3-(1-methylpiperidin-4-yl)propionyl]-1,2-cyclohexanediaminehydrochloride

[1293]

[1294] 1)(±)-cis-N¹-[3-[1-(tert-Butoxycarbonyl)piperidin-4-yl]propionyl]-N²-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminewas obtained from1-(tert-butoxycarbonyl)-4-[2-(methoxycarbonyl)ethyl]piperidine (J. Med.Chem., 1998, Vol. 41, p. 2492) in a similar manner to the step 1) ofExample 83.

[1295]¹H-NMR (CDCl₃) δ: 1.00-1.17(2H,m), 1.30-1.80(11H,m), 1.44(9H,s),1.80-1.95(1H,m), 2.10-2.23(1H,m), 2.29(2H,t,J=7.8 Hz), 2.50-2.70(2H,m),3.90-4.18(3H,m), 4.23(1H,br.s), 6.05(1H,br,J=6.0 Hz), 6.85(1H,d,J=2.0Hz), 7.22(1H,dd,J=8.8,1.8 Hz), 7.37(1H,d,J=8.8 Hz), 7.62(1H,d,J=1.8 Hz),7.89(1H,br.s), 9.59(1H,s). MS (ESI) m/z: 531(M+H)⁺.

[1296] 2) The title compound was obtained from the product describedabove in a similar manner to the step 2) of Example 83.

[1297]¹H-NMR (DMSO-d₆) δ: 1.20-1.90(15H,m), 2.10-2.26(1H,m), 2.55(3H,s),2.55-2.70(2H,m), 3.21(2H,t,J=12.0 Hz), 4.00-4.16(2H,m),7.18(1H,dd,J=8.8,2.2 Hz), 7.21(1H,s), 7.44(1H,d,J=8.8 Hz),7.70(1H,d,J=2.2 Hz), 7.82(1H,br,J=6.9 Hz), 8.11(1H,br,J=7.6 Hz),10.02(1H,br.s), 11.94(1H,s). MS (ESI) m/z: 445(M+H)⁺.

Example 85(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(1-methylpiperidin-4-yl)propioloyl]-1,2-cyclohexane-diamine

[1298]

[1299] 1)(±)-cis-N¹-[[1-(tert-Butoxycarbonyl)piperidin-4-yl]propioloyl]-N²-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminewas obtained from1-(tert-butoxycarbonyl)-4-(methoxycarbonylethynyl)piperidine in asimilar manner to the step 1) of Example 83.

[1300]¹H-NMR (DMSO-d₆) δ: 1.30-1.82(12H,m), 1.38(9H,s), 2.68-2.78(1H,m),2.96-3.10(2H,m), 3.56-3.66(2H,m), 4.00-4.20(2H,m), 7.16(1H,s),7.18(1H,dd,J=8.6,2.0 Hz), 7.43(1H,d,J=8.6 Hz), 7.70(1H,d,J=2.0 Hz),7.91(1H,br,J=7.3 Hz), 8.25(1H,br,J=7.8 Hz), 11.81(1H,s).

[1301] 2) The title compound was obtained from the product describedabove in a similar manner to the step 2) of Example 83.

[1302]¹H-NMR (DMSO-d₆) δ: 1.30-1.45(2H,m), 1.45-1.70(6H,s),1.70-1.82(4H,m), 1.90-2.03(2H,m), 2.10(3H,s), 2.40-2.52(1H,m),2.52-2.62(2H,m), 4.04-4.18(2H,m),7.15(1H,s), 7.18(1H,dd,J=8.8,2.0 Hz),7.43(1H,d,J=8.8 Hz), 7.71(1H,d,J=2.0 Hz), 7.92(1H,br,J=7.3 Hz),8.25(1H,br,J=7.8 Hz),11.83(1H,s). MS (FAB) m/z: 441(M+H)⁺.

Example 86(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)propioloyl]-1,2-cyclohexanediamine

[1303]

[1304] 1)(±)-cis-N¹-[[1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]propioloyl]-N²-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminewas obtained from1-(tert-butoxycarbonyl)-4-(methoxycarbonylethynyl)-1,2,3,6-tetrahydropyridinein a similar manner to the step 1) of Example 83.

[1305]¹H-NMR (DMSO-d₆) δ: 1.35-1.82(8H,m), 1.39(9H,s), 2.15-2.23(2H,m),3.40(2H,t,J=5.4 Hz), 3.92(2H,br.s), 4.14(2H,br.s), 6.29(1H,br.s),7.16(1H,s), 7.18(1H,dd,J=8.7,2.1 Hz), 7.43(1H,d,J=8.7 Hz),7.71(1H,d,J=2.1 Hz), 7.92(1H,br,J=7.3 Hz), 8.40(1H,br,J=8.3 Hz),11.80(1H,s). MS (ESI) m/z: 525(M+H)⁺.

[1306] 2) The title compound was obtained from the product describedabove in a similar manner to the step 2) of Example 83.

[1307]¹H-NMR (DMSO-d₆) δ: 1.30-1.46(2H,m), 1.46-1.84(6H,s),2.15-2.25(2H,m), 2.21(3H,s), 2.42(2H,t,J=5.6 Hz), 2.89-2.97(2H,m),4.13(2H,br.s), 6.25(1H,br.s), 7.15(1H,s), 7.17(1H,d,J=8.6 Hz),7.43(1H,d,J=8.6 Hz), 7.70(1H,s), 7.97(1H,br,J=7.8 Hz), 8.41(1H,br,J=7.8Hz), 11.84(1H,s) MS (FAB) m/z: 439(M+H)⁺.

Example 87(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[[1-(4-pyridyl)piperidin-4-yl]carbonyl]-1,2-cyclohexanediaminehydrochloride

[1308]

[1309] 1-(4-Pyridyl)piperidine-4-carboxylic acid (Tetrahedron, 1998,Vol. 44, p. 7095) (206 mg) was suspended in dichloromethane (50 ml),thionyl chloride (144 μl) was added under ice cooling, and the mixturewas stirred for 30 minutes. After triethylamine (969 μl) was added tothe reaction mixture,(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride (328 mg) was added, and the mixture was stirred at roomtemperature for 30 minutes. After the reaction mixture was concentratedunder reduced pressure, and water was added to the residue, the solutionwas concentrated under reduced pressure, and precipitate deposited wascollected by filtration to obtain the title compound (310 mg) as a palebrown solid.

[1310]¹H-NMR (DMSO-d₆) δ: 1.30-2.00(10H,m), 2.74(1H,br.s),3.18(2H,q,J=12.3 Hz), 4.03(1H,br.s), 4.10-4.25(3H,m), 7.15-7.55(4H,m),7.42(1H,d,J=8.8 Hz), 7.65(1H,s), 7.91(1H,d,J=8.8 Hz), 8.20-8.35(3H,m),11.91(1H,s), 13.47(1H,br.s) MS (FAB)m/z: 480(M+H)⁺.

Example 88 (±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[[4-(morpholinomethyl)thiazol-2-yl]carbonyl]-1,2-cyclohexanediaminehydrochloride

[1311]

[1312] The title compound was obtained from(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and lithium 4-(morpholinomethyl)thiazole-2-carboxylate ina similar manner to Example 2.

[1313]¹H-NMR (DMSO-d₆) δ: 1.35-1.55(2H,m), 1.55-1.80(4H,m),1.95-2.15(2H,m), 3.00-3.60(4H,m), 3.85-4.00(4H,m), 4.15-4.35(2H,m),4.40-4.65(2H,m), 7.18(1H,dd,J=8.8.2.1 Hz), 7.30(1H,s), 7.41(1H,d,J=8.8Hz), 7.65(1H,d,J=2.1 Hz), 8.19(1H,s), 8.35-8.50(2H,m), 11.01(1H,br.s),11.94(1H,br.s). MS (FAB) m/z: 502(M+H)⁺.

Example 89(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[[5-[(N,N-dimethylamino)methyl]thiazol-2-yl]carbonyl]-1,2-cyclohexanediaminehydrochloride

[1314]

[1315] The title compound was obtained from(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and lithium5-[(N,N-dimethylamino)-methyl]thiazole-2-carboxylate in a similar mannerto Example 2.

[1316]¹H-NMR (DMSO-d₆) δ: 1.35-1.55(2H,m), 1.55-1.80(4H,m),1.85-2.10(2H,m), 2.72(6H,br.s), 4.17-4.35(2H,m), 4.62(2H,br.s),7.16-7.10(2H,m), 7.43(1H,d,J=8.8 Hz), 7.71(1H,d,J=1.7 Hz), 8.10(1H,s),8.15(1H,d,J=7.8 Hz), 8.52(1H,d,J=7.8 Hz), 10.70-10.80(1H,br),11.86(1H,br.s). MS (FAB) m/z: 460(M+H)⁺.

Example 90(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(4,5,6,7-tetrahydro-5,6-trimethylenethiazolo[4,5-d]pyridazin-2-yl]carbonyl]-1,2-cyclohexanediaminehydrochloride

[1317]

[1318] The title compound was obtained from(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and lithium4,5,6,7-tetrahydro-5,6-trimethylenethiazolo[4,5-d]pyridazine-2-carboxylatein a similar manner to Example 2.

[1319]¹H-NMR (DMSO-d₆) δ: 1.35-1.50(2H,m), 1.61(4H,br.s),1.80-2.00(2H,m), 2.27(2H,br.s), 2.80-4.80(10H,m), 7.14(1H,d,J=1.5 Hz),7.17(1H,dd,J=8.5,2.0 Hz), 7.41(1H,d,J=8.5 Hz), 7.70(1H,d,J=2.0 Hz),8.09(1H,d,J=7.3 Hz), 8.44(1H,br.s), 11.81(1H,br.s). MS (FAB) m/z:499(M+H)⁺.

Example 91(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(4,5,6,7-tetrahydro-5,6-tetramethylenethiazolo[4,5-d]pyridazin-2-yl]carbonyl]-1,2-cyclohexanediaminehydrochloride

[1320]

[1321] The title compound was obtained from lithium4,5,6,7-tetrahydro-5,6-tetramethylenethiazolo[4,5-d]-pyridazine-2-carboxylateand (±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride in a similar manner to Example 2.

[1322]¹H-NMR (DMSO-d₆) δ: 1.35-1.55(2H,m), 1.55-2.10(10H,m),2.80-4.80(10H,m), 7.10-7.25(2H,m), 7.42(1H,d,J=8.8 Hz), 7.72(1H,d,J=1.7Hz), 8.12(1H,br.s), 8.41(1H,br.s), 11.83(1H,br.s). MS (FAB) m/z:513(M+H)⁺.

Example 92(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1323]

[1324]2-Bromo-5-tert-butoxycarbonyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole (171mg) was dissolved in diethyl ether (5 ml) in an argon atmosphere, andthe solution was cooled to −78° C., to which n-butyllithium (1.60Nhexane solution, 385 μl) was added dropwise. After the reaction mixturewas stirred for 10 minutes at −78° C., and carbon dioxide was blown intothe reaction mixture for 20 minutes, it was allowed to room temperature.After the reaction mixture was concentrated under reduced pressure, theresidue was dissolved in N,N-dimethylformamide (10 ml) To the solution,were added(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride (184 mg), 1-hydroxy-benzbtriazole monohydrate (76 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (215 mg).The resultant mixture was stirred for 3 days. The reaction mixture wasconcentrated, and dichloromethane and a saturated aqueous solution ofsodium hydrogencarbonate were added to the residue to separate anorganic layer. The organic layer was dried over anhydrous sodiumsulfate, and the solvent was then distilled off under reduced pressure.The resultant residue was purified by column chromatography on silicagel (methanol:dichloromethane=3:97) to obtain(±)-cis-N¹-[(5-tert-butoxycarbonyl-4,6-dihydro-5H-pyrrolo[3,4-d]-thiazol-2-yl)carbonyl]-N²-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine(44 mg). After a saturated ethanol solution (5 ml) of hydrochloric acidwas added to the thus-obtained product, the mixture was stirred at roomtemperature for 1 hour, and the reaction mixture was concentrated, ethylacetate was added to the residue to solidify it. The resultant powderwas collected by filtration to obtain the title compound (31 mg) ascolorless powder.

[1325]¹H-NMR (DMSO-d₆) δ: 1.35-1.52(2H,m),1.55-1.80(4H,m),1.82-2.05(2H,m), 4.22(1H,br.s), 4.28(1H,br.s), 4.38(2H,s),4.56(2H,s),7.14-7.20(2H,m), 7.42(1H,d,J=8.6 Hz), 7.71(1H,d,J=1.7 Hz),8.10(1H,d,J=7.1 Hz), 8.45(1H,d,J=7.8 Hz), 10.10-10.50(2H,br),11.83(1H,br.s). MS (FAB) m/z: 444(M+H)⁺.

Example 93(1S,2R)-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1326]

[1327] The title compound was obtained from(1S,2R)-N¹-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine andlithium 5-methyl-4,6-dihydro-5H-pyrrolo[3,4-d]-thiazole-2-carboxylate ina similar manner to Example 2.

[1328] [α]_(D)+110 ° (24.8°, c=1.20, DMSO). ¹H-NMR (DMSO-d₆) δ:1.35-1.50(2H,m), 1.63(4H,br.s), 1.85-2.10(2H,m), 3.02(3H,br.s),4.15-4.80(6H,m), 7.10-7.22(2H,m), 7.42(1H,d,J=8.8 Hz), 7.71(1H,d,J=1.7Hz), 8.10(1H,d,J=6.8 Hz), 8.46(1H,d,J=7.8 Hz), 11.83(1H,br.s),11.97(1H,br.s). MS (FAB) m/z: 458(M+H)⁺.

Example 94(±)-cis-N¹-[[6-(tert-Butoxycarbonyl)-5,7-dihydropyrrolo-[3,4-d]pyrimidin-2-yl]carbonyl]-N²-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine

[1329]

[1330] After6-(tert-Butoxycarbonyl)-5,7-dihydro-2-methoxycarbonylpyrrolo[3,4-d]pyrimidinewas hydrolyzed with lithium hydroxide, it was reacted with(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride in a similar manner to Example 2 to obtain the titlecompound.

[1331]¹H-NMR (CDCl₃) δ: 1.54(9H,s), 1.55-2.30(8H,m), 4.23(1H,br.s),4.53(1H,br.s), 4.74-4.83(4H,m), 6.99(1H,d,J=1.5 Hz),7.19(1H,dd,J=8.8,2.1 Hz), 7.34(1H,d,J=8.8 Hz), 7.62(1H,d,J=2.1 Hz),8.11(1H,br.s), 8.48-8.53(1H,br), 8.70-8.76(1H,br), 9.60-9.70(1H,br). MS(ESI) m/z: 539(M+H)⁺.

Example 95(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[[5,7-dihydro-6-methylpyrrolo[3,4-d]pyrimidin-2-yl]carbonyl]-1,2-cyclohexanediaminehydrochloride

[1332]

[1333] The title compound was obtained from(±)-cis-N¹-[[6-(tert-butoxycarbonyl)-5,7-dihydropyrrolo[3,4-d]-pyrimidin-2-yl]carbonyl]-N²-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminein a similar manner to Example 83.

[1334]¹H-NMR (DMSO-d₆) δ: 1.40-1.55(2H,m), 1.55-1.75(4H,m),1.80-2.05(2H,m), 2.98(3H,br.s), 4.28(2H,br.s), 4.65(4H,br.s),7.14-7.20(2H,m), 7.41(1H,d,J=8.8 Hz), 7.69(1H,d,J=2.0 Hz),8.17(1H,d,J=6.9 Hz), 8.65(1H,d,J=8.3 Hz), 8.93(1H,s), 11.73(1H,br.s),11.82(1H,br.s) MS (FAB) m/z: 453(M+H)⁺.

Example 96(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N¹,N²-dimethyl-N²-[[5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-1,2-cyclohexanediamine

[1335]

[1336] Lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate (653mg) was suspended in dichloromethane (10 ml), a 1N ethanol solution (3.2ml) of hydrochloric acid was added, and the mixture was stirred forseveral minutes. The solvent was then distilled off under reducedpressure. Chloroform (15 ml) was added to the residue, and thionylchloride (7 ml) and N,N-dimethylformamide (one drop) were added to stirthe mixture at 65° C. for 4 hours. The solvent was distilled off underreduced pressure, and a solution (14 ml) of(±)-cis-N¹-[(1-benzenesulfonyl-5-chloroindol-2-yl)carbonyl]-N¹,N²-dimethyl-1,2-cyclohexanediamine(847 mg) in a 1:1 mixed solvent (14 ml) of dichloromethane and pyridinewas added to the residue to stir the mixture overnight at roomtemperature. Water was added to the reaction mixture to separate anorganic layer. The organic layer was washed with water and then driedover anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by flash columnchromatography on silica gal (dichloromethane:methanol=47:3). Theresultant pale yellow solid was dissolved in methanol (10 ml), andpotassium hydroxide (98 mg) was added to stir the mixture at roomtemperature for 10 hours. The solvent was distilled off under reducedpressure, and a saturated aqueous solution of sodium hydrogencarbonatewas added to conduct extraction with dichloromethane. The resultantorganic layer was dried over anhydrous sodium sulfate. After the residuewas purified by flash column chromatography on silica gal(dichloromethane:methanol=47:3), the resultant pale yellow solid wasdissolved in dichloromethane (5 ml), and a 1N ethanol solution (528 μl)of hydrochloric acid was added. Ethyl acetate was added and the solventwas distilled off under reduced pressure to obtain the title compound(267 mg) as a white solid.

[1337]¹H-NMR (DMSO-d₆) δ: 1.59-2.07(8H,m), 2.82(3H,m), 3.07-3.48(10H,m),4.26-4.50(2H,m), 4.94(1H,s), 5.27(1H,br.s), 6.61(1H,s), 7.13(1H,d,J=8.6Hz), 7.43(1H,br.s), 7.57(1H,s), 11.25(1H,br.s), 12.90(1H,br.s). MS (ESI)m/z: 500(M+H)⁺.

Example 97(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1338]

[1339] The title compound was obtained from(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and lithium5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylatein a similar manner to Example 2.

[1340]¹H-NMR (DMSO-d₆) δ: 1.39-1.52(2H,m), 1.62(4H,br.s),1.86-2.09(2H,m), 3.03(2H,br.s), 3.40-3.47(2H,m), 4.17-4.32(2H,m),4.44(2H,s), 7.15(1H,s), 7.17(1H,dd,J=8.6,2.0 Hz), 7.41(1H,d,J=8.6 Hz),7.71(1H,s), 8.10-8.15(1H,m), 8.40-8.47(1H,m), 9.69(2H,br.s),11.85(1H,s). MS (FAB) m/z: 458(M+H)⁺.

Example 98(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-ethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1341]

[1342] The title compound was obtained by ethylating(±)-cis-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride with ethyl iodide in a similar manner to Example 52.

[1343]¹H-NMR (DMSO-d₆) δ: 1.31(3H,t,J=7.1 Hz), 1.45(2H,br.s),1.62(4H,br.s), 1.82-2.10(2H,m), 3.00-3.52(5H,m), 3.71(1H,br.s),4.15-4.50(3H,m), 4.68-4.82(1H,m), 7.15(1H,s), 7.17(1H,dd,J=8.8,2.0 Hz),7.41(1H,d,J=8.8 Hz), 7.71(1H,d,J=2.0 Hz), 8.14(1H,br.s),8.36-8.55(1H,m), 11.32(1H,br.s), 11.86(1H,s). MS (FAB) m/z: 486(M+H)⁺.

Example 99(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[[5-(2-methoxyethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-1,2-cyclohexanediaminehydrochloride

[1344]

[1345] The title compound was obtained from(±)-cis-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and 2-methoxyethyl bromide in a similar manner to Example52.

[1346]¹H-NMR (DMSO-d₆) δ: 1.44(2H,br.s), 1.62(4H,br.s), 1.85-2.10(2H,m),2.76-3.21(6H,m), 3.28(3H,s), 3.64(2H,br.s), 4.00-4.52(4H,m), 7.14(1H,s),7.17(1H,dd,J=8.8,2.0 Hz), 7.41(1H,d,J=8.8 Hz), 7.70(1H,d,J=2.0 Hz),8.08-8.20(1H,m), 8.36-8.48(1H,m), 11.84(1H,s). MS (FAB) m/z: 516(M+H)⁺.

Example 100(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-methoxycarbonylmethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[1347]

[1348] The title compound was obtained from(±)-cis-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and methyl bromoacetate in a similar manner to Example 52.

[1349]¹H-NMR (CDCl₃) δ: 1.52-1.98(7H,m), 2.17(1H,br.s), 2.87-3.10(4H,m),3.49(2H,s), 3.76(3H,s), 3.93(1H,d,J=15.4 Hz), 3.99(1H,d,J=15.4 Hz),4.22(1H,br.s), 4.45(1H,br.s), 6.86(1H,d,J=1.2 Hz), 7.18(1H,dd,J=8.8,2.0Hz), 7.33(1H,d,J=8.8 Hz), 7.58-7.63(2H,m), 7.87(1H,br.s), 9.88(1H,br.s). MS (FAB) m/z: 530(M+H)⁺.

Example 101(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1350]

[1351] The title compound was obtained from(±)-cis-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and acetone in a similar manner to Example 45.

[1352]¹H-NMR (DMSO-d₆) δ: 1.18-1.73(8H,m), 1.81-2.10(2H,m),2.97-3.16(1H,m), 3.20-3.41(2H,m), 3.52-3.80(2H,m), 4.19-4.31(2H,m),4.34-4.77(2H,m), 7.17(1H,s), 7.18(1H,dd,J=8.8,2.0 Hz), 7.42(1H,d,J=8.8Hz), 7.71(1H,d,J=2.0 Hz), 8.15(1H,br.s), 8.28-8.51(1H,m),11.31(1H,br.s), 11.86(1H,s). MS (FAB) m/z: 500(M+H)⁺.

Example 102(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[[5-(2,3,5,6-tetrahydro-4H-pyran-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-1,2-cyclohexanediaminehydrochloride

[1353]

[1354] The title compound was obtained from(±)-cis-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and tetrahydro-4H-pyran-4-one in a similar manner toExample 45.

[1355]¹H-NMR (DMSO-d₆) δ: 1.30-3.56(19H,m), 3.70-4.01(3H,m),4.17-4.30(2H,m), 4.32-4.80(1H,m), 7.15(1H,s), 7.17(1H,dd,J=8.6,2.0 Hz),7.41(1H,d,J=8.6 Hz), 7.71(1H,d,J=2.0 Hz), 8.14(1H,br.s), 8.39(1H,br.s),11.84 (1H,s) MS (FAB) m/z: 542(M+H)⁺.

Example 103(±)-cis-N¹-[[5-[2-(tert-Butoxycarbonylamino)ethyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl]carbonyl]-N²-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexane-diamine

[1356]

[1357] The title compound was obtained from(±)-cis-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and N-(tert-butoxycarbonyl)aminoacetoaldehyde (J. Org.Chem., 1988, Vol. 53, p.3457) in a similar manner to Example 45.

[1358]¹H-NMR (CDCl₃) δ: 1.44(9H,s), 1.54-1.98(7H,m), 2.10-2.20(1H,m),2.74(2H,br.s), 2.92(4H,br.s), 3.34(2H,br.s), 3.84(2H,br.s),4.21(1H,br.s), 4.45(1H,br.s), 6.86(1H,s), 7.19(1H,dd,J=8.8,2.0 Hz),7.33(1H,d,J=8.8 Hz), 7.57-7.63(2H,m), 7.81(1H,br.s), 9.66(1H,br.s). MS(FAB) m/z: 601(M+H)⁺.

Example 104(±)-cis-N¹-[[5-(2-Aminoethyl)-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl]carbonyl]-N²-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1359]

[1360](±)-cis-N¹-[[5-[2-(tert-Butoxycarbonylamino)-ethyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-N²-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine(450 mg) was dissolved in dichloromethane (5 ml), and a saturatedethanol solution (30 ml) of hydrochloric acid was added to stir themixture at room temperature for 1 minute. The reaction mixture wasconcentrated under reduced pressure, ethyl acetate was added to theresidue, and solids deposited were collected by filtration to obtain thetitle compound (367 mg) as a pale yellow amorphous solid.

[1361]¹H-NMR (DMSO-d₆) δ: 1.38-1.50(2H,m), 1.61(4H,br.s),1.85-2.08(2H,m), 3.00-4.62(12H,m), 7.14(1H,s), 7.16(1H,dd,J=8.8,2.0 Hz),7.41(1H,d,J=8.8 Hz), 7.69(1H,d,J=2.0 Hz), 8.12(1H,d,J=6.6 Hz),8.15-8.68(4H,m), 11.85(1H,s). MS (FAB) m/z: 501(M+H)⁺.

Example 105(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[[5-[2-(methanesulfonylamino)ethyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl]carbonyl]-1,2-cyclohexane-diaminehydrochloride

[1362]

[1363](±)-cis-N¹-[[5-(2-Aminoethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-N²-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride (110 mg) was dissolved in pyridine (3 ml), methanesulfonylchloride (30 μl) was added, and the mixture was stirred overnight atroom temperature. The reaction mixture was concentrated under reducedpressure, and a 85:15 mixed solvent of dichloromethane and methanol, andwater were added to conduct liquid separation. The resultant organiclayer was dried over anhydrous sodium sulfate. The solvent was distilledoff under reduced pressure, and the residue was purified by columnchromatography on silica gel (dichloromethane:methanol=100:3) to obtaina pale yellow foamy substance. This product was suspended in 1Nhydrochloric acid (0.3 ml), and the suspension was concentrated underreduced pressure to obtain the title compound (63 mg) as a pale yellowfoamy substance.

[1364]¹H-NMR (DMSO-d₆) δ: 1.38-1.50(2H,m), 1.55-1.70(4H,m),1.86-2.05(2H,m), 2.97(3H,s), 3.02-3.25(2H,m), 3.30-3.60(5H,m),3.78(1H,br.s), 4.18-4.30(2H,m), 4.45-4.86(2H,m), 7.14(1H,s),7.16(1H,dd,J=8.8,2.0 Hz), 7.40(1H,d,J=8.8 Hz), 7.41(1H,br.s),7.69(1H,d,J=2.0 Hz), 8.09(1H,br.s), 8.43(1H,br.s), 11.18(1H,br.s),11.82(1H,s). MS (FAB) m/z: 579(M+H)⁺.

Example 106(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[[5-[2-(methoxycarbonylamino)ethyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl]carbonyl]-1,2-cyclohexane-diaminehydrochloride

[1365]

[1366](±)-cis-N¹-[[5-(2-Aminoethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-N²-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride (144 mg) was dissolved in pyridine (3 ml), triethylamine(138 μl) was added, and the mixture was stirred at room temperature for5 minutes. A solution prepared by adding triphosgene (49 mg) totetrahydrofuran (1 ml) containing methanol (20 μl) was added dropwise tothis solution. The reaction mixture was stirred at room temperature for1 hour, then concentrated under reduced pressure, and the residue wasdissolved in a 9:1 mixed solvent of dichloromethane and methanol. Waterwas added to the solution to conduct liquid separation. The resultantorganic layer was dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (dichloromethane:methanol=100:3) toobtain a colorless foamy substance. This product was suspended in 1Nhydrochloric acid (0.2 ml), and the suspension was concentrated underreduced pressure to obtain the title compound (60 mg) as a pale yellowfoamy substance.

[1367]¹H-NMR (DMSO-d₆) δ: 1.38-1.50(2H,m), 1.61(4H,br.s),1.85-2.04(2H,m), 2.80-3.49(8H,m), 3.52(3H,s), 3.62-4.91(4H,m),7.14(1H,s), 7.16(1H,dd,J=8.8,2.0 Hz), 7.37(1H,br.s), 7.40(1H,d,J=8.8Hz), 7.70(1H,s), 8.11(1H,d,J=6.8 Hz), 8.40(1H,br.s.), 11.05(1H,br.s),11.82(1H,br.s). MS (FAB) m/z: 559(M+H)⁺.

Example 107(±)-cis-N¹-[[5-[2-(Acetylamino)ethyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-N²-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1368]

[1369](±)-cis-N¹-[[5-(2-Aminoethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-N²-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride (90 mg) was dissolved in N,N-dimethylformamide (3 ml),triethylamine (65 μl) and acetic anhydride (22 μl) were added, and themixture was stirred overnight at room temperature. The reaction mixturewas concentrated under reduced pressure, and dichloromethane and a 0.3Naqueous solution of sodium hydroxide were added to the residue toconduct liquid separation. The resultant organic layer was dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, and the residue was purified by column chromatography onsilica gel (dichloromethane:methanol=100:3) to obtain a colorless foamysubstance. This product was suspended in 1N hydrochloric acid (0.3 ml),and the suspension was concentrated under reduced pressure to obtain thetitle compound (73 mg) as a pale yellow foamy substance.

[1370]¹H-NMR (DMSO-d₆) δ: 1.39-1.52(2H,m), 1.54-1.70(4H,m), 1.83(3H,s),1.84-2.06(2H,m), 3.02-3.87(8H,m), 4.16-4.32(2H,m), 4.40-4.52(1H,m),4.78-4.88(1H,m), 7.14(1H,s), 7.16(1H,d,J=8.6 Hz), 7.40(1H,d,J=8.6 Hz),7.70(1H,s), 8.07-8.17(1H,m), 8.22-8.30(1H,m), 8.38-8.52(1H,m),11.14(1H,br.s), 11.83(1H,s). MS (FAB) m/z: 543(M+H)⁺.

Example 108(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[[5-(2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-1,2-cyclohexanediamine

[1371]

[1372] The title compound was obtained from(±)-cis-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and 2-bromoethanol in a similar manner to Example 52.

[1373]¹H-NMR (DMSO-d₆) δ: 1.37-1.69(6H,m), 1.86-2.03(2H,m),2.54-2.61(2H,m), 2.75-2.86(4H,m), 3.52-3.59(2H,m), 3.75(2H,s),4.47(1H,t,J=5.4 Hz), 7.12(1H,s), 7.16(1H,dd,J=8.8,2.0 Hz),7.40(1H,d,J=8.8 Hz), 7.70(1H,s), 8.05-8.13(1H,m), 8.28-8.35(1H,m),11.78(1H,s). MS (FAB) m/z: 502(M+H)⁺.

Example 109(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[[5-(3-hydroxypropyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-1,2-cyclohexanediaminehydrochloride

[1374]

[1375] The title compound was obtained from(±)-cis-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and 3-bromopropanol in a similar manner to Example 52.

[1376]¹H-NMR (DMSO-d₆) δ: 1.45(2H,br.s) , 1.56-1.71(4H,m)1.87-2.10(4H,m), 3.05-3.55(7H,m), 3.70-3.80(1H,m), 4.19-4.32(2H,m),4.40-4.50(1H,m) ,4.74-4.84(1H,m), 7.12-7.20(2H,m), 7.41(1H,d,J=8.8 Hz),7.70(1H,s), 8.08-8.16(1H,m), 8.40-8.51(1H,m), 10.98(1H,br.s),11.82(1H,s) MS (FAB) m/z: 516(M+H)⁺.

Example 110(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-butyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1377]

[1378] The title compound was obtained from(±)-cis-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and n-butyl bromide in a similar manner to Example 52.

[1379]¹H-NMR (DMSO-d₆) δ: 0.88(3H,t,J=7.2 Hz), 1.20-1.70(10H,m),1.87-2.05(2H,m), 2.55-3.40(8H,m), 4.16-4.30(2H,m), 7.13(1H,s),7.16(1H,d,J=8.8 Hz), 7.40(1H,d,J=8.8 Hz), 7.69(1H,s), 8.05-8.14(1H,m),8.35(1H,br.s), 11.81(1H,s). MS (FAB) m/z: 514(M+H)⁺.

Example 111(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-isobutyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1380]

[1381] The title compound was obtained from(±)-cis-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and isobutyl iodide in a similar manner to Example 52.

[1382]¹H-NMR (DMSO-d₆) δ: 0.80-1.05(7H,m), 1.38-1.50(2H,m),1.54-1.70(4H,m), 1.89-2.02(2H,m), 2.52-3.77(8H,m), 4.18-4.31(2H,m),7.17(1H,dd,J=8.8,2.0 Hz), 7.40(1H,d,J=8.8 Hz), 7.69(1H,s),8.05-8.13(1H,m), 8.27-8.53(1H,m), 11.81(1H,s). MS (FAB) m/z: 514(M+H)⁺.

Example 112(±)-cis-N¹-[(5-Acetyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl]carbonyl]-N²-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine

[1383]

[1384] (±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-1,2-cyclohexanediaminehydrochloride (100 mg) was dissolved in N,N-dimethylformamide (3 ml),triethylamine (84 μl) and acetic anhydride (29 μl) were added, and themixture was stirred at room temperature for 3 hours. The reactionmixture was concentrated under reduced pressure, and dichloromethane and1N hydrochloric acid were added to the residue to conduct liquidseparation. The resultant organic layer was dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, and theresidue was purified by column chromatography on silica gel(dichloromethane:methanol=100:3) to obtain the title compound (86 mg) asa pale yellow foamy substance.

[1385]¹H-NMR (CDCl₃) δ: 1.52-1.85(5H,m), 1.91(2H,br.s), 2.10-2.28(4H,m),2.77-3.00(2H,m), 3.70-4.00(2H,m), 4.19-4.38(1H,m), 4.45(1H,br.s),4.68-4.99(2H,m), 6.85(1H,s), 7.17-7.22(1H,m), 7.30-7.39(1H,m),7.50-7.84(3H,m), 9.72-10.05(1H,m). MS (FAB) m/z: 500(M+H)⁺.

Example 113(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-methanesulfonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[1386]

[1387](±)-cis-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-carbonyl]-1,2-cyclohexanediaminehydrochloride (100 mg) was dissolved in pyridine (3 ml), triethylamine(168 μl) and methanesulfonyl chloride (48 μl) were added, and themixture was stirred overnight at room temperature. The reaction mixturewas concentrated under reduced pressure, and dichloromethane and 1Nhydrochloric acid were added to the residue to separate an organiclayer. The resultant organic layer was dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, and theresidue was purified by column chromatography on silica gel(dichloromethane:methanol=100:1) to obtain the title compound (79 mg) asa pale yellow foamy substance.

[1388]¹H-NMR (CDCl₃) δ: 1.50-1.82(5H,m), 1.90(2H,br.s), 2.13(1H,br.s),2.89(3H,s), 2.91-2.98(2H,m), 3.60-3.70(2H,m), 4.30(1H,br.s),4.44(1H,br.s),4.58(2H,s), 6.87(1H,s), 7.19(1H,d,J=8.8 Hz),7.34(1H,d,J=8.8 Hz), 7.61(3H,br.s), 9.91(1H,br.s). MS (FAB) m/z:536(M+H)⁺.

Example 114(±)-cis-N¹-[(5-Methylindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1389]

[1390] The title compound was obtained from(±)-cis-N-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and 5-methylindole-2-carboxylic acid in a similar mannerto Example 6.

[1391]¹H-NMR (DMSO-d₆) δ: 1.35-1.50(2H,m), 1.50-1.80(4H,m),1.85-2.07(2H,m), 2.36(3H,s),2.88(3H,s), 3.12(2H,br.s), 3.53(2H,br.s),4.15-4.30(2H,m), 4.30-4.80(2H,br), 7.00(1H,dd,J=8.4,1.5 Hz),7.05(1H,d,J=1.5 Hz), 7.30(1H,d,J=8.4 Hz), 7.38(1H,s), 8.00(1H,d,J=7.3Hz), 8.43(1H,br.s), 11.45(1H,br.s), 11.49(1H,br.s). MS (FAB) m/z:452(M+H)⁺.

Example 115(±)-cis-N¹-[(6-Chloro-4-hydroxynaphthalen-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1392]

[1393] The title compound was obtained from(±)-cis-N-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and 6-chloro-4-hydroxynaphthalene-2-carboxylic acid in asimilar manner to Example 6.

[1394]¹H-NMR (DMSO-d₆) δ: 1.44-1.63(6H,m), 1.98-1.99(2H,m), 2.87(3H,s),3.08(2H,br.s), 3.52(2H,br.s), 4.22(2H,br.s), 4.74(2H,br.s), 7.26(1H,s),7.55-7.57(1H,m), 7.82(1H,s), 7.99(1H,d,J=9.0 Hz), 8.10(1H,s),8.22(1H,d,J=5.9 Hz), 8.49(1H,br.s), 10.65(1H,s), 11.33(1H,br.s). MS(FAB) m/z: 485(M+H)⁺.

Example 116(±)-cis-N¹-[(6-Chloroimidazo[1,2-a]pyridin-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1395]

[1396] Ethyl 6-chloroimidazo[1,2-a]pyridine-2-carboxylate (JapanesePatent Application Laid-Open No. 11-500123 through PCT route) (150 mg)was dissolved in tetrahydrofuran (4 ml), and water (1 ml) and lithiumhydroxide (18 mg) were added at room temperature to stir the mixture for1 hour. The reaction mixture was concentrated under reduced pressure toobtain crude lithium 6-chloroimidazo[1,2-a]pyridine-2-carboxylate. Thisproduct was dissolved in N,N-dimethylformamide (4.0 ml), and(±)-cis-N-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexane-diaminehydrochloride (232 mg), 1-hydroxybenzotriazole monohydrate (180 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (256 mg) andtriethylamine (371 μl) were added to this solution to stir the mixtureat room temperature for 3 days. The reaction mixture was concentratedunder reduced pressure, and water and a saturated aqueous solution ofsodium hydrogencarbonate were added to the residue to conduct extractionwith dichloromethane. The resultant organic layer was then dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The resultant residue was purified by columnchromatography on silica gel(dichloromethane:acetone=1:1→dichloromethane:acetone:methanol=5:5:1) toobtain a white solid. To this solid, were added dichloromethane,methanol and 1N hydrochloric acid, and the resultant mixture wasconcentrated to obtain the title compound (224 mg) as a pale brownsolid.

[1397]¹H-NMR (DMSO-d₆) δ: 1.35-1.51(2H,m), 1.51-1.70(4H,m),1.86-2.05(2H,m), 2.87(3H,s), 3.00-3.15(1H,m), 3.15-3.30(1H,m),3.35-3.50(1H,m), 3.44(1H,br.s), 3.65(1H,br.s), 4.10-4.32(2H,m),4.32-4.45(1H,m), 4.58-4.70(1H,m), 7.60-7.70(1H,m), 7.75(1H,d,J=9.5 Hz),8.50-8.60(2H,m), 8.60-8.70(1H,m), 9.08(1H,d,J=15.9 Hz),11.75-11.98(1H,br). MS (FAB) m/z: 473(M+H)⁺.

Example 117(±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-cyclohexene-1,2-diaminehydrochloride

[1398]

[1399] The title compound was obtained from(±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-4-cyclohexene-1,2-diamine andlithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxylate in asimilar manner to Example 2.

[1400]¹H-NMR (DMSO-d₆) δ: 2.43-2.34(m,4H), 2.50(s,3H), 3.11(m,2H),3.42(m,1H), 3.65(m,1H), 4.20(m,1H), 4.30(m,2H), 4.64(m,1H), 5.66(s,2H),7.02(s,1H), 7.15(dd,1H,J=1.5,8.8 Hz), 7.39(d,1H,J=8.5 Hz), 7.68(s,1H),8.34(d,1H,J=8.5 Hz), 8.69(d,1H,J=8.8 Hz), 11.72(s,1H). MS (ESI) m/z:470(M+H)⁺.

Example 118(1R*,2S*,4R*)—N¹-[(5-chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-N²-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[1401]

[1402](1R*,2S*,4R*)—N2-tert-Butoxycarbonyl-N¹-[(5-chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-1,2-cyclohexanediamine(1.40 g) was suspended in ethanol (8 ml), and a saturated ethanolsolution (10 ml) of hydrochloric acid was added at room temperature tostir the mixture for 12 hours. The solvent was distilled off underreduced pressure to obtain(1R*,2S*,4R*)—N¹-[(5-chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-1,2-cyclohexanediaminehydrochloride (1.25 g) as a colorless solid.

[1403] The title compound was obtained from the above-described productand lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in asimilar manner to Example 2.

[1404]¹H-NMR (CDCl₃) δ: 1.29(3H,t,J=7.1 Hz), 1.52-1.80(2H,m),2.03-2.37(4H,m), 2.53(3H,s), 2.57-2.71(1H,m), 3.73 and 3.78(each 1H,eachd,J=14.4 Hz), 4.08-4.17(1H,m), 4.18(2H,q,J=7.2 Hz), 4.55-4.65(1H,m),6.85(1H,br.s), 7.21(1H,dd,J=8.8,2.0 Hz), 7.33(1H,d,J=8.8 Hz),7.48(1H,d,J=7.6 Hz), 7.63(1H,d,J=2.0 Hz), 7.98(1H,d,J=7.6 Hz),9.30(1H,s). MS (ESI) m/z: 544(M+H)⁺.

Example 119(1S,2R,4S)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-N²-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[1405](1S,2R,4S)—N²-tert-Butoxycarbonyl-N¹-[(5-chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-1,2-cyclohexanediamine(4.2 g) was suspended in ethanol (25 ml), and a saturated ethanolsolution (55 ml) of hydrochloric acid was added at room temperature tostir the mixture for 11 hours. The solvent was distilled off underreduced pressure to obtain(1S,3R,4S)—N¹-[(5-chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-1,2-cyclohexanediaminehydrochloride (4.15 g) as a colorless solid.

[1406](1S,2R,4S)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-1,2-cyclohexanediaminehydrochloride (4.15 g) was dissolved in N,N-dimethylformamide (40 ml),and lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxylate (2.86g), 1-hydroxybenzotriazole monohydrate (1.72 g) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.15 g)were added to this solution at room temperature to stir the mixture for39 hours. The reaction mixture was concentrated under reduced pressure,and water was added to the residue to conduct extraction withchloroform. The resultant organic layer was washed with saturated salineand dried over anhydrous magnesium sulfate. The solvent was distilledoff under reduced pressure, and the resultant residue was purified bycolumn chromatography on silica gel (chloroform:methanol=100:1) toobtain the title compound (1.71 g) as a colorless amorphous substance.

[1407] [α]_(D)−94° (C=1.0, chloroform).

Example 120(1R*,2R*,4S*)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-N²-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[1408]

[1409](1R*,2R*,4S*)—N²-tert-Butoxycarbonyl-N¹-[(5-chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-1,2-cyclohexanediaminewas treated with a saturated ethanol solution of hydrochloric acid andthen condensed with lithium5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]-pyridine-2-carboxylate in asimilar manner to Example 118 to obtain the title compound.

[1410]¹H-NMR (CDCl₃) δ: 1.29(3H,t,J=7.10 Hz) , 1.43-1.86(3H,m),2.19-2.35(2H,m), 2.46(3H,s), 2.45-2.60(1H,m), 2.67-2.80(1H,m),2.80-2.98(4H,m), 3.58 and 3.71(each 1H,each d,J=15.2 Hz),3.80-3.95(1H,m), 4.10-4.40(3H,m), 6.86(1H,br.s), 7.14-7.22(1H,m),7.22-7.34(2H,m), 7.47(1H,d,J=6.8 Hz), 7.60(1H,s), 9.35(1H,s). MS (ESI)m/z: 544(M+H)⁺.

Example 121(1R*,2S*,4S*)—N²-[(5-Chloroindol-2-yl)carbonyl]-4-methoxycarbonyl-N¹-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[1411]

[1412](1R*,2S*,4S*)—N¹-tert-Butoxycarbonyl-N²-[(5-chloroindol-2-yl)carbonyl]-4-methoxycarbonyl-1,2-cyclohexanediaminewas treated with a saturated ethanol solution of hydrochloric acid andthen condensed with lithium5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]-pyridine-2-carboxylate in asimilar manner to Example 118 to obtain the title compound.

[1413]¹H-NMR (DMSO-d₆) δ: 1.55-1.80(3H,m), 1.80-2.20(3H,m),2.60-2.75(1H,m), 2.92(3H,s), 3.15-3.30(1H,m), 3.30-3.50(4H,m),3.57(3H,s), 3.55-3.70(1H,m), 4.20-4.30(1H,m), 4.30-4.40(1H,m),7.02(1H,s), 7.17(1H,dd,J=8.5,2.0 Hz), 7.41(1H,d,J=8.5 Hz), 7.71(1H,s),8.20-8.35(1H,m), 8.35-8.45(1H,m), 11.82(1H,br). MS (FAB) m/z: 530(M+H)⁺.

Example 122(1R*,2S*,4R*)—N²-[(5-Chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-N¹-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[1414]

[1415](1R*,2S*,4R*)—N²-tert-Butoxycarbonyl-4-ethoxycarbonyl-N¹-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminewas treated with a saturated ethanol solution of hydrochloric acid andthen condensed with 5-chloroindole-2-carboxylic acid in a similar mannerto Example 118 to obtain the title compound.

[1416]¹H-NMR (CDCl₃) δ: 1.29(3H,t,J=7.1 Hz), 1.82-2.30(6H,m),2.49(3H,s), 2.62-2.73(1H,m), 3.74-3.85(2H,m), 3.85-3.93(2H,m),3.71(2H,s), 4.12-4.29(3H,m), 4.49-4.59(1H,m), 6.89(1H,br.s),7.21(1H,dd,J=8.8and2.0 Hz), 7.32(1H,d,J=8.8 Hz), 7.33(1H,br.s),7.41(1H,br.s), 7.62(1H,br.s), 9.37(1H,s). MS (ESI) m/z: 544(M+H)⁺.

Example 123(1R*,2S*,4S*)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-methoxycarbonyl-N²-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1417]

[1418](1R*,2S*,4S*)—N¹-tert-Butoxycarbonyl-4-methoxycarbonyl-N²-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminewas treated with a 4N dioxane solution of hydrochloric acid and thencondensed with 5-chloroindole-2-carboxylic acid in a similar manner toExample 118 to obtain the title compound.

[1419]¹H-NMR (DMSO-d₆) δ: 1.65-1.80(3H,m), 1.80-2.10(2H,m),2.15-2.25(1H,m), 2.55-2.70(1H,m), 2.89(3H,s), 3.05-3.20(1H,m),3.30-3.50(4H,m), 3.55-3.65(1H,m), 3.62(3H,s), 4.20-4.30(1H,m),4.35-4.45(1H,m), 7.19(1H,dd,J=8.8,1.2 Hz), 7.23(1H,s), 7.43(1H,d,J=8.8Hz), 7.73(1H,s), 8.03(1H,d,J=6.8 Hz), 8.73(1H,d,J=8.5 Hz), 11.85(1H,s).MS (FAB) m/z: 530(M+H)⁺.

Example 124(1S,2R,4R)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-methoxycarbonyl-N²-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1420]

[1421](1S,2R,4R)—N¹-tert-Butoxycarbonyl-4-methoxycarbonyl-N²-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminewas treated with a 4N dioxane solution of hydrochloric acid and thencondensed with 5-chloroindole-2-carboxylic acid in a similar manner toExample 118 to obtain the title compound.

[1422]¹H-NMR (DMSO-d₆) δ: 1.67-1.76(3H,m), 1.88-1.91(1H,m),2.01(1H,br.s), 2.13-2.22(1H,m), 2.52-2.67(4H,m), 2.86(2H,br.s),3.04(2H,br.s), 3.33-3.41(1H,m), 3.61(3H,s), 4.22-4.36(3H,m),7.17-7.22(2H,m), 7.42(1H,d,J=8.8 Hz), 7.72(1H,s), 8.00(1H,d,J=6.9 Hz),8.68(1H,d,J=8.6 Hz), 11.80(1H,s). MS (FAB) m/z: 530(M+H)⁺.

Example 125(1S,2R,4R)—N¹-[(5-Fluoroindol-2-yl)carbonyl]-4-methoxycarbonyl-N²-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1423]

[1424](1S,2R,4R)—N¹-tert-Butoxycarbonyl-4-methoxycarbonyl-N²-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminewas treated with a 4N dioxane solution of hydrochloric acid and thencondensed with 5-fluoroindole-2-carboxylic acid in a similar manner toExample 118 to obtain the title compound.

[1425]¹H-NMR (CD₃OD) δ: 1.81-1.90(3H,m), 2.09-2.17(3H,m), 2.61(3H,s),2.60-2.63(1H,m), 2.95(2H,br.s), 3.10-3.12(2H,m), 3.45-3.49(1H,m),3.69(3H,s), 4.28-4.69(3H,m), 6.99-7.04(1H,m), 7.16(1H,s),7.29(1H,dd,J=9.8,2.5 Hz), 7.41(1H,dd,J=8.8,4.6 Hz). MS (FAB) m/z:514(M+H)⁺.

Example 126(1S,2R,4S)-4-Ethoxycarbonyl-N¹-[(5-fluoroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[1426]

[1427](1S,2R,4S)—N²-tert-Butoxycarbonyl-4-ethoxycarbonyl-N¹-[(5-fluoroindol-2-yl)carbonyl]-1,2-cyclohexanediaminewas treated with a 4N dioxane solution of hydrochloric acid and thencondensed with lithium5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxylate in asimilar manner to Example 118 to obtain the title compound.

[1428]¹H-NMR (CD₃OD) δ: 1.29(3H,t,J=7.1 Hz), 1.60-2.34(6H,m),2.53(3H,s), 2.61-2.68(1H,m), 2.80-2.88(2H,m), 2.96-2.99(2H,m),3.75(2H,s), 4.12-4.14(1H,m), 4.18(2H,q,J=7.1 Hz), 4.59-4.60(1H,m),6.86(1H,s), 6.99-7.04(1H,m), 7.27-7.34(2H,m), 7.47(1H,d,J=7.1 Hz),7.92(1H,d,J=5.6 Hz), 9.13(1H,s). MS (FAB) m/z: 528(M+H)⁺.

Example 127 (1R*,2S*,4R*,5S* or1R*,2S*,4S*,5R*)-4,5-Bis(methoxycarbonyl)-N¹(orN²)-[(5-chloroindol-2-yl)carbonyl]-N²(orN¹)-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-1,2-cyclohexanediamine

[1429]

[1430] Dimethyl (1R*,2S*,4R*,5S* or1R*,2S*,4S*,5R*)-4,5-bis(tert-butoxycarbonylamino)-1,2-cyclohexane-dicarboxylate(350 mg) was dissolved in methanol (30 ml), and a saturated methanolsolution of hydrochloric acid was added to stir the mixture at roomtemperature for 9 hours. The solvent was distilled off under reducedpressure to obtain crude dimethyl4,5-diamino-1,2-cyclohexanedicarboxylate. This product was dissolved inN,N-dimethylformamide (50 ml), and 5-chloroindole-2-carboxylic acid (120mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (120mg), 1-hydroxybenzotriazole monohydrate (140 mg) and N-methylmorpholine(0.13 ml) were added to the solution to stir the mixture at roomtemperature for 17 hours. The solvent was distilled off under reducedpressure, and water was added to the residue to conduct extraction withdichloromethane. The resultant organic layer was washed with saturatedaqueous solution of sodium chloride and dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, and theresultant residue was purified by column chromatography on silica gel(methanol:dichloromethane=1:9) to obtain crude(1R*,2S*,4R*,5S* or1R*,2S*,4S*,5R*)-4,5-bis(methoxycarbonyl)-N¹(orN²)-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine (190 mg). Thisproduct was dissolved in N,N-dimethylformamide (50 ml), and lithium5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxylate (280mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (130mg) and 1-hydroxybenzotriazole monohydrate (210 mg) were added to stirthe mixture at room temperature for 17 hours. The solvent was distilledoff under reduced pressure, and water was added to the residue toconduct extraction with dichloromethane. The resultant organic layer waswashed with saturated aqueous solutiono of sodium chloride and driedover anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the resultant residue was purified by columnchromatography on silica gel (methanol:dichloromethane=1:9) andpreparative chromatography to obtain the title compound (22 mg) as whitepowder.

[1431]¹H-NMR (DMSO-d₆) δ: 1.97-1.99(2H,m), 2.33-2.36(2H,m), 2.39(3H,s),2.68-3.69(8H,m), 3.88(3H,s), 3.89(3H,s), 4.18(1H,br), 4.28(1H,br),7.01(1H,s), 7.16-7.19(2H,m), 7.40-7.42(2H,m), 7.74(1H,s), 11.81(1H,s) MS(FAB) m/z: 588(M+H)⁺.

Example 128(1R*,2S*,4R*)-4-Carboxy-N¹-[(5-chloroindol-2-yl)-carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[1432]

[1433](1R*,2S*,4R*)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-N²-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexane-diamine(916 mg) was suspended in a mixed solvent of ethanol (10 ml) andtetrahydrofuran (8 ml), and a 1N aqueous solution (3.3 ml) of sodiumhydroxide was added at room temperature to stir the mixture for 12 hoursat the same temperature. After adding 1N hydrochloric acid (3.3 ml), thesolvent was distilled off under reduced pressure, and the residue waswashed with water and ether to obtain the title compound (712 mg) as acolorless solid.

Example 129(1R,2R,4S)-4-Carboxy-N¹-[(5-chloroindol-2-yl)-carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[1434]

[1435](1R,2R,4S)—N¹-(5-Chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-N²-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexane-diamine(1.6 g) was suspended in a mixed solvent of ethanol (20 ml) andtetrahydrofuran (15 ml), and a 1N aqueous solution (5.9 ml) of sodiumhydroxide was added at room temperature to stir the mixture for 12 hoursat the same temperature. After adding 1N hydrochloric acid (5.9 ml), thesolvent was distilled off under reduced pressure, and the residue waswashed with water and ether to obtain the title compound (1.19 g) as acolorless solid.

[1436] m.p. 234-236° C. [α]_(D-)−57° (C=1.0, methanol).

Example 130(1R*,2S*,4S*)-4-Carboxy-N¹-[(5-chloroindol-2-yl)-carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1437]

[1438](1R*,2S*,4S*)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-methoxycarbonyl-N²-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexane-diamine(180 mg) was dissolved in a mixed solvent of tetrahydrofuran (8 ml) andwater (2 ml), and lithium hydroxide (17 mg) was added to stir themixture at room temperature for 45 minutes. After adding 1N hydrochloricacid, the reaction mixture was concentrated under reduced pressure, asmall amount of water was added to the residue, and solids depositedwere collected by filtration to obtain the title compound (140 mg) as apale yellow solid.

[1439]¹H-NMR (DMSO-d₆) δ: 1.60-1.80(3H,m), 1.80-1.95(1H,m),1.95-2.20(2H,m), 2.41(3H,s), 2.70-2.90(4H,m), 3.70-3.85(2H,m),4.15-4.30(1H,m), 4.30-4.40(1H,m), 7.19(1H,dd,J=8.8,2.2 Hz),7.22(1H,d,J=1.5 Hz), 7.43(1H,d,J=8.8 Hz), 7.72(1H,d,J=2.2 Hz),8.00(1H,d,J=6.8 Hz), 8.64(1H,d,J=8.5 Hz), 11.82(1H,s). MS (FAB) m/z:516(M+H)⁺.

Example 131(1R*,2R*,4S*)-4-Carboxy-N¹-[(5-chloroindol-2-yl)-carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[1440]

[1441](1R*,2R*,4S*)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-N²-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexane-diamine(244 mg) was suspended in a mixed solvent of ethanol (8 ml) andtetrahydrofuran (5 ml), and a 1N aqueous solution (0.9 ml) of sodiumhydroxide was added at room temperature to stir the mixture for 12hours. After adding 1N hydrochloric acid (0.9 ml), the solvent wasdistilled off under reduced pressure, and the residue was washed withwater and ether to obtain the title compound (152 mg) as a colorlesssolid.

[1442]¹H-NMR (DMSO-d₆) δ: 1.44-2.23(6H,m), 2.34(3H,s), 2.60-2.90(5H,m),3.53 and 3.62(each 1H,each d,J=5.65 Hz), 3.95-4.25(2H,m), 7.02(1H,s),7.12(1H,br,J=8.8 Hz), 7.36(1H,d,J=8.8 Hz), 8.29(1H,d,J=8.8 Hz),8.40(1H,d,J=8.8 Hz), 11.65(1H,s). MS (ESI) m/z: 516(M+H)⁺.

Example 132(1R*,2S*,4S*)-4-Carboxy-N²-[(5-Chloroindol-2-yl)-carbonyl]-N¹-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminelithium salt:

[1443]

[1444](1R*,2S*,4S*)—N²-[(5-Chloroindol-2-yl)carbonyl]-4-methoxycarbonyl-N¹-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexane-diamine(1.2 g) was dissolved in tetrahydrofuran (32 ml), and lithium hydroxide(60.8 mg) and water (4 ml) were successively added under ice cooling tostir the mixture at room temperature for 14 hours. The solvent wasdistilled off under reduced pressure to obtain the title compound (1.12g).

[1445]¹H-NMR (DMSO-d₆) δ: 1.55-1.70(2H,m), 1.70-2.05(4H,m),2.10-2.20(1H,m), 2.25-2.40(4H,m), 2.50-2.80(4H,m), 3.45-3.65(3H,m),4.10-4.30(2H,m), 7.00-7.20(2H,m), 7.50-7.65(2H,m).

Example 133(1R*,2S*,4R*)-4-Carbamoyl-N¹-[(5-chloroindol-2-yl)-carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[1446]

[1447](1R*,2S*,4R*)—N²-(tert-Butoxycarbonyl)-4-carbamoyl-N¹-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminewas treated with a 4N dioxane solution of hydrochloric acid and thencondensed with lithium5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxylate in asimilar manner to Example 118 to obtain the title compound.

[1448]¹H-NMR (CDCl₃) δ: 0.78-2.40(7H,m), 2.53(3H, s), 2.80-2.89(1H,m),2.91-3.00(1H,m), 3.68-3.76(2H,m), 4.08-4.19(1H,m), 4.54-4.65(1H,m),6.80(1H,br.s), 7.21(1H,dd,J=8.4 and 1.6 Hz), 7.33(1H,d,J=8.4 Hz),7.38-7.43(1H,m), 7.49-7.55(1H,m), 7.63(1H,br.s), 9.14(1H,br.s). MS (ESI)m/z: 515(M+H)⁺.

Example 134(1R*,2S*,4R*)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1449]

[1450] Triethylamine (0.25 ml), dimethylamine hydrochloride (133 mg),1-hydroxybenzotriazole monohydrate (53 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (75 mg) wereadded to a chloroform suspension (10 ml) of(1R*,2S*,4R*)-4-carboxy-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(168 mg), and the mixture was stirred for 72 hours. The solvent wasdistilled off under reduced pressure, and water was added to the residueto conduct extraction with chloroform. The resultant organic layer waswashed with saturated aqueous solution of sodium chloride and dried overanhydrous magnesium sulfate. The solvent was distilled off under reducedpressure, and the resultant residue was purified by columnchromatography on silica gel (dichloromethane:methanol=93:7). Thethus-obtained colorless solid (135 mg) was suspended in ethanol (5 ml),to which 1N hydrochloric acid (0.5 ml) was added. The mixture wasstirred for 2 hours, and the solvent was distilled off to obtain thetitle compound (112 mg) as colorless powder.

[1451]¹H-NMR (DMSO-d₆) δ: 1.42-2.07(6H,m), 2.73-3.70(10H,m), 2.88(3H,s),2.97(3H,s), 4.03-4.20(1H,m), 4.51-4.67(1H,m), 7.04(1H,br.s),7.16(1H,br,J=8.8 Hz), 7.41(1H,d,J=8.8 Hz), 7.68(1H,br.s),8.32-8.47(2H,m), 10.76(1H,br.s). MS (ESI) m/z: 543(M+H)⁺.

Example 135(1R*,2R*,4S*)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1452]

[1453] The title compound was obtained from(1R*,2R*,4S*)-4-carboxy-N¹-[(5-chloroindol-2-yl)-carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamineand dimethylamine hydrochloride in a similar manner to Example 134.

[1454]¹H-NMR (DMSO-d₆) δ: 1.00-2.05(7H,m), 2.50(3H,s), 2.81(3H,s),2.92-3.65(9H,m), 3.95-4.10(1H,m), 4.50-4.68(1H,m), 7.08(1H,s),7.13(1H,dd,J=8.8,2.0 Hz), 7.37(1H,d,J=8.8 Hz), 7.66(1H,br.s),8.31(1H,d,J=8.4 Hz), 8.50(1H,d,J=9.2 Hz), 11.67(1H,s). MS (ESI) m/z:543(M+H)⁺.

Example 136(1R*,2S*,4S*)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1455]

[1456] The title compound was obtained from(1R*,2S*,4S*)-4-carboxy-N¹-[(5-chloroindol-2-yl)-carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamineand dimethylamine hydrochloride in a similar manner to Example 134.

[1457]¹H-NMR (DMSO-d₆) δ: 1.42-2.25(7H,m), 2.80-3.12(4H,m), 2.82(3H,s),2.88(3H,s), 3.04(3H,s), 3.32-3.68(2H,m), 4.29-4.61(2H,m),7.16-7.24(2H,m), 7.42(1H,d,J=8.8 Hz), 7.74(1H,s), 8.01(1H,d,J=5.6 Hz),8.91(1H,d,J=8.4 Hz), 11.85(1H,br.s). MS (ESI) m/z: 543(M+H)⁺.

Example 137(1R*,2S*,4R*)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-(N-methylcarbamoyl)-N²-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexane-diaminehydrochloride

[1458]

[1459] The title compound was obtained from(1R*,2S*,4R*)-4-carboxy-N¹-[(5-chloroindol-2-yl)-carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamineand methylamine hydrochloride in a similar manner to Example 134.

[1460]¹H-NMR (DMSO-d₆) δ: 1.50-2.70(7H,m), 2.90(3H,s), 3.05-3.75(9H,m),4.05-4.20(1H,m), 4.38-4.53(1H,m), 7.03(1H,br.s), 7.16(1H,br,J=8.8 Hz),7.41(1H,d,J=8.8 Hz), 7.69(1H,br.s), 8.11(1H,br.s), 8.39(1H,d,J=7.6 Hz),11.78(1H,br.s). MS (ESI) m/z: 529(M+H)⁺.

Example 138(1S,2R,4S)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-(N-isopropylcarbamoyl)-N²-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexane-diaminehydrochloride

[1461]

[1462] The title compound was obtained from(1S,2R,4S)-4-carboxy-N¹-[(5-chloroindol-2-yl)-carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamineand isopropylamine in a similar manner to Example 134.

[1463]¹H-NMR (DMSO-d₆) δ: 1.02(6H,dd,J=6.5,2.5 Hz), 1.50-2.10(6H,m),2.30(1H,t,J=12.0 Hz), 2.91(3H,s), 3.10-3.75(4H,m), 3.75-3.90(1H,m),4.07-4.20(1H,m), 4.30-4.57(2H,br.s), 4.57-4.83(1H,br.s), 7.03(1H,d,J=1.5Hz), 7.16(1H,dd,J=8.8,2.1 Hz), 7.41(1H,d,J=8.8 Hz), 7.60-7.75(2H,m),8.05(1H,br.s), 8.43(1H,br,J=7.8 Hz), 11.63(1H,br.s), 11.79(1H,s). MS(FAB) m/z: 557(M+H)⁺.

Example 139(1S,2R,4S)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-(N-cyclopropylcarbamoyl)-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1464]

[1465] The title compound was obtained from(1S,2R,4S)-4-carboxy-N¹-[(5-chloroindol-2-yl)-carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamineand cyclopropylamine in a similar manner to Example 134.

[1466]¹H-NMR (DMSO-d₆) δ: 0.32-0.40(2H,m), 0.53-0.63(2H,m),1.50-2.10(6H,m), 2.25-2.40(1H,m), 2.45-2.70(2H,m), 2.91(3H,s),3.05-3.80(3H,m), 4.05-4.17(1H,m), 4.30-4.55(2H,m), 4.55-4.80(1H,m),7.03(1H,d,J=1.5 Hz), 7.16(1H,dd,J=8.8,2.0 Hz), 7.41(1H,d,J=8.8 Hz),7.68(1H,d,J=2.0 Hz), 7.86(1H,br,J=3.4 Hz), 8.06(1H,br.s),8.40(1H,br,J=7.6 Hz), 11.20-11.60(1H,br), 11.79(1H,s). MS (FAB) m/z:555(M+H)⁺.

Example 140(1S,2R,4S)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-(N-ethyl-N-methylcarbamoyl)-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1467]

[1468] The title compound was obtained from(1S,2R,4S)-4-carboxy-N¹-[(5-chloroindol-2-yl)-carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamineand ethylmethylamine in a similar manner to Example 134.

[1469]¹H-NMR (DMSO-d₆) δ: 0.93-1.13(3H,m), 1.40-1.64(1H,m),1.64-1.88(3H,m), 1.88-2.10(2H,m), 2.76(1/2 of 3H,s), 2.90(3H,s),2.93(1/2 of 3H,s), 3.10-3.80(7H,m), 4.05-4.17(1H,m), 4.30-4.85(3H,m),7.04(1H,s), 7.15(1H,dd,J=8.8,1.7 Hz), 7.40(1H,d,J=8.8 Hz), 7.67(1H,s),8.30-8.50(2H,m), 11.29(1H,br.s), 11.77(1H,s). MS (FAB) m/z: 557(M+H)⁺.

Example 141(1S,2R,4S)—N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-(pyrrolidinocarbonyl)-1,2-cyclohexane-diaminehydrochloride

[1470]

[1471] The title compound was obtained from(1S,2R,4S)-4-carboxy-N¹-[(5-chloroindol-2-yl)-carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamineand pyrrolidine in a similar manner to Example 134.

[1472]¹H-NMR (DMSO-d₆) δ: 1.45-2.10(10H,m), 2.75-2.90(2H,m), 2.90(3H,s),3.10-3.70(H,m), 4.05-4.20(1H,m), 4.25-4.80(3H,m), 7.05(1H,s),7.17(1H,d,J=8.7 Hz), 7.41(1H,d,J=8.7 Hz), 7.69(1H,s), 8.32(1H,br,J=7.6Hz), 8.38(1H,br,J=7.1 Hz), 11.22(1H,br.s), 11.78(1H,s). MS (FAB) m/z:569(M+H)⁺.

Example 142(1R*,2S*,4R*)—N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-(4-morpholinocarbonyl)-1,2-cyclohexane-diaminehydrochloride

[1473]

[1474] The title compound was obtained from(1R*,2S*,4R*)-4-carboxy-N¹-[(5-chloroindol-2-yl)-carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamineand morpholine in a similar manner to Example 134.

[1475]¹H-NMR (DMSO-d₆) δ: 1.40-2.05(6H,m), 2.75-3.70(18H,m)4.02-4.17(1H,m), 4.55-4.69(1H,m), 7.05(1H,br.s), 7.17(1H,br,J=8.8 Hz),7.41(1H,d,J=8.8 Hz), 7.67(1H,br.s), 8.35(1H,d,J=7.6 Hz), 8.40(1H,d,J=7.6Hz), 10.79(1H,br.s). MS (ESI) m/z: 585(M+H)⁺.

Example 143(1S,2R,4S)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-(N-ethylcarbamoyl)-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1476]

[1477](1S,2R,4S)-4-Carboxy-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(150 mg) was dissolved in N,N-dimethylformamide (3 ml), to whichN-ethylamine hydrochloride (119 mg), 1-hydroxybenzotriazole monohydrate(79 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(112 mg) and triethylamine (326 μl) were added, and the mixture wasstirred at room temperature for 4 days. The solvent was distilled offunder reduced pressure, and a saturated aqueous solution of sodiumhydrogencarbonate was added to the residue to conduct extraction withdichloromethane. The resultant organic layer was dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure,and the resultant residue was purified by flash column chromatography onsilica gel (dichloromethane:methanol=47:3). The thus-obtained whitesolid was dissolved in dichloromethane, to which 1N ethanol solution(171 μl) of hydrochloric acid was added. The solvent was distilled offunder reduced pressure, and methanol and diethyl ether were added to theresidue to collect precipitate formed by filtration, thereby obtainingthe title compound (74 mg) as white solid.

[1478]¹H-NMR (DMSO-d₆) δ: 0.99(3H,t,J=7.2 Hz), 1.57-2.02(6H,m),2.33-2.38(1H,m), 2.92(3H,s), 3.01-3.08(2H,m), 3.17-3.20(2H,s),3.45-3.70(2H,m), 4.10-4.17(1H,m), 4.40-4.69(3H,m), 7.04(1H,d,J=2.0 Hz),7.17(1H,dd,J=8.8,2.0 Hz), 7.41(1H,d,J=8.8 Hz), 7.69(1H,d,J=2.0 Hz),7.78-7.81(1H,m), 8.08-8.12(1H,m), 8.40(1H,d,J=8.1 Hz), 11.23(1H,br.s),11.79(1H,br.s). MS (FAB) m/z: 543(M+H)⁺.

Example 144(1S,2R,4S)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1479]

[1480](1S,2R,4S)-4-Carboxy-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(900 mg) was dissolved in N,N-dimethylformamide (50 ml), to whichdimethylamine hydrochloride (304 mg), 1-hydroxybenzotriazole monohydrate(262 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(369 mg) and diisopropylethylamine (1.83 ml) were added, and the mixturewas stirred at room temperature for 12 hours. The solvent was distilledoff under reduced pressure, and a saturated aqueous solution of sodiumhydrogencarbonate was added to the residue to conduct extraction withdichloromethane. The resultant organic layer was dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure,and the resultant residue was purified by flash column chromatography onsilica gel (dichloromethane:methanol=47:3). The thus-obtained whitesolid was dissolved in dichloromethane, to which 1N ethanol solution(1.49 ml) of hydrochloric acid was added. The solvent was distilled offunder reduced pressure, and methanol and diethyl ether were added to theresidue to collect precipitate formed by filtration, thereby obtainingthe title compound (777 mg) as white solid.

[1481] [α]_(D)=−53.9° (18° C., c=0.505, methanol).

[1482]¹H-NMR (DMSO-d₆) δ: 1.45-1.60(1H,m), 1.70-1.85(3H,m), 2.80(3H,s),2.91(3H,s), 2.95-3.10(1H,m), 2.97(3H,s), 3.10-3.75(4H,m),4.05-4.15(1H,m), 4.35-4.75(3H,m), 7.05(1H,s), 7.16(1H,dd,J=8.7,2.1 Hz),7.41(1H,d,J=8.6 Hz), 7.67(1H,s), 8.30-8.45(2H,m), 11.63(1H,br),11.78(1H,s). MS (FAB) m/z: 543(M+H)⁺.

Example 145(1S,2R,4S)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-(N,N-diethylcarbamoyl)-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1483]

[1484] The title compound was obtained from(1S,2R,4S)-4-carboxy-N¹-[(5-chloroindol-2-yl)-carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamineand diethylamine in a similar manner to Example 134.

[1485]¹H-NMR (DMSO-d₆) δ: 0.99, 1.05(6H, each t, J=7.1 Hz),1.53-1.61(1H,m), 1.74-1.80(3H,m), 1.96-2.05(2H,m), 2.88-2.95(4H,m),3.17-3.67(8H,m), 4.11-4.16(1H,m), 4.45(1H,br.s), 4.55-4.58(1H,m),4.66(1H,br.s), 7.06(1H,d,J=2.0 Hz), 7.16(1H,dd,J=8.9,1.9 Hz),7.42(1H,d,J=8.9 Hz),7.69(1H,d,J=1.9 Hz), 8.41(2H,d,J=7.8 Hz),11.65(1H,br.s), 11.81(1H,br.s). MS (FAB) m/z: 571(M+H)⁺.

Example 146(1S,2R,4S)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-(N-methyl-N-propylcarbamoyl)-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1486]

[1487] The title compound was obtained from(1S,2R,4S)-4-carboxy-N¹-[(5-chloroindol-2-yl)-carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamineand N-methyl-N-propylamine in a similar manner to Example 134.

[1488]¹H-NMR (DMSO-d₆) δ: 0.71,0.79(3H,each t,J=7.3 Hz) 1.41-1.75(6H,m),1.99(2H,br.s), 2.67-3.02(7H,m), 3.11-3.40(4H,m), 3.47(1H,br.s),3.67(1H,br.s), 4.12(1H,br.s), 4.44-4.68(3H,m), 7.05(1H,s),7.16(1H,dd,J=8.8,1.7 Hz), 7.41(1H,d,J=8.8 Hz), 7.69(1H,d,J=1.7 Hz),8.35-8.42(2H,m), 11.45(1H,br.s), 11.79, 11.81(1H,each s). MS (FAB) m/z:571(M+H)⁺.

Example 147(1S,2R,4S)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-(N,N-dipropylcarbamoyl)-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1489]

[1490] The title compound was obtained from(1S,2R,4S)-4-carboxy-N¹-[(5-chloroindol-2-yl)-carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamineand dipropylamine in a similar manner to Example 134.

[1491]¹H-NMR (DMSO-d₆) δ: 0.69(3H,t,J=7.3 Hz), 0.79(3H,t,J=7.3 Hz),1.38-1.47(4H,m), 1.57-1.78(4H,m), 1.98-2.01(2H,m), 2.80(1H,t,J=11.5 Hz),3.01-3.39(6H,m), 3.48(1H,br.s), 3.68(1H,br.s), 4.13-4.16(1H,m),4.43(1H,br.s), 4.48-4.50(1H,m), 4.68(1H,br.s), 7.04(1H,d,J=2.0 Hz),7.16(1H,dd,J=8.8,2.2 Hz), 7.41(1H,d,J=8.8 Hz), 7.70(1H,d,J=2.2 Hz),8.33(1H,d,J=7.6 Hz), 11.27-11.40(1H,m), 11.80(1H,br.s). MS (FAB) m/z:599(M+H)⁺.

Example 148(1S,2R,4S)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-(N-isopropyl-N-methylcarbamoyl)-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1492]

[1493] The title compound was obtained from(1S,2R,4S)-4-carboxy-N¹-[(5-chloroindol-2-yl)-carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamineand N-isopropyl-N-methylamine in a similar manner to Example 134.

[1494]¹H-NMR (DMSO-d₆) δ: 0.99-1.15(6H,m) , 1.50-1.99(6H,m), 2.64,2.78(3H,each s), 2.92(3H,s), 2.96-3.39(4H,m), 3.47(1H,br.s),3.68(1H,br.s), 4.12-4.13(1H,m), 4.45(1H,br.s), 4.58-4.70(2H,m),7.05(1H,s), 7.16(1H,dd,J=8.8,2.0 Hz), 7.41(1H,d,J=8.8 Hz),7.69(1H,d,J=2.0 Hz), 8.38-8.46(2H,m), 11.27(1H,br.s), 11.79(1H,br.s). MS(FAB) m/z: 571(M+H)⁺.

Example 149(1S,2R,4S)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-[N-(2-methoxyethyl)-N-methylcarbamoyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1495]

[1496] The title compound was obtained from(1S,2R,4S)-4-carboxy-N¹-[(5-chloroindol-2-yl)-carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamineand N-(2-methoxyethyl)-N-methylamine in a similar manner to Example 134.

[1497]¹H-NMR (DMSO-d₆) δ: 1.50-1.99(6H,m), 2.80, 3.01(3H,each s),2.91(3H,s), 3.03(1H,br.s), 3.16(2H,s), 3.23(3H,s), 3.35-3.67(6H,m),4.09-4.16(1H,m), 4.43-4.67(3H,m), 7.04-7.06(1H,m), 7.16(1H,dd,J=8.8,2.0Hz), 7.42(1H,d,J=8.8 Hz), 7.69(1H,br.s), 8.29-8.41(2H,m),11.59(1H,br.s), 11.80(1H,br.s). MS (FAB) m/z: 587(M+H)⁺.

Example 150(1S,2R,4S)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-[N-(2-hydroxyethyl)-N-methylcarbamoyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1498]

[1499] The title compound was obtained from(1S,2R,4S)-4-carboxy-N¹-[(5-chloroindol-2-yl)-carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamineand N-(2-hydroxyethyl)-N-methylamine in a similar manner to Example 134.

[1500]¹H-NMR (DMSO-d₆) δ: 1.50-1.55(1H,m), 1.74-1.84(3H,m),1.94-1.97(2H,m), 2.67,3.02(3H,each s), 2.91(3H,s), 3.10-3.68(9H,m),4.11-4.13(1H,m), 4.43-4.66(4H,m), 7.05(1H,s), 7.16(1H,dd,J=8.7,2.0 Hz),7.41(1H,d,J=8.7 Hz), 7.68(1H,s), 8.34-8.40(2H,m), 11.47(1H,br.s),11.79(1H,s). MS (FAB) m/z: 573(M+H)⁺.

Example 151(1S,2R,4S)-4-[(Azetidin-1-yl)carbonyl]-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1501]

[1502] The title compound was obtained from(1S,2R,4S)-4-carboxy-N¹-[(5-chloroindol-2-yl)-carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamineand azetidine hydrochloride in a similar manner to Example 134.

[1503]¹H-NMR (DMSO-d₆) δ: 1.47-1.55(1H,m), 1.65-1.82(3H,m),1.88-2.01(2H,m), 2.16(2H,quint.,J=7.6 Hz), 3.17-3.67(5H,m),3.82(2H,t,J=7.6 Hz), 4.02-4.14(3H,m), 4.43-4.67(3H,m), 7.06(1H,s),7.17(1H,dd,J=8.7,1.7 Hz), 7.41(1H,d,J=8.7 Hz), 7.69(1H,br.s),8.31(1H,d,J=7.6 Hz), 8.38(1H,d,J=7.6 Hz), 11.41(1H,br.s), 11.80(1H,s).MS (FAB) m/z: 555(M+H)⁺.

Example 152(1S,2R,4S)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-[[(3S)-3-fluoropyrrolidin-1-yl]carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1504]

[1505] The title compound was obtained from(1S,2R,4S)-4-carboxy-N¹-[(5-chloroindol-2-yl)-carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamineand (S)-3-fluoropyrrolidine (Synlett., 1995, p. 55) in a similar mannerto Example 134.

[1506]¹H-NMR (DMSO-d₆) δ: 1.23-3.77(22H,m), 4.11-4.16(1H,m)4.58-4.51(1H,m), 5.23-5.42(1H,m), 7.05(1H,s), 7.16(1H,d,J=8.3 Hz),7.42(1H,d,J=8.3 Hz), 7.68(1H,s), 8.34-8.37(2H,m), 11.78(1H,s). MS (FAB)m/z: 587(M+H)⁺.

Example 153(1R*,2S*,4S*)—N²-[(5-Chloroindol-2-yl)carbonyl]-4-(N-methylcarbamoyl)-N¹-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[1507]

[1508] The title compound was obtained from(1R*,2S*,4S*)-4-carboxy-N²-[(5-chloroindol-2-yl)carbonyl]-N¹-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminelithium salt and methylamine in a similar manner to Example 134.

[1509]¹H-NMR (DMSO-d₆) δ: 1.50-1.80(4H,m), 1.90-2.05(2H,m),2.35-2.45(4H,m), 2.59(3H,d,J=4.4 Hz), 2.70-2.80(2H,m), 2.85-2.95(2H,m),3.64(2H,s), 4.20-4.35(2H,m), 7.02(1H,s), 7.16(1H,d,J=8.6 Hz),7.41(1H,d,J=8.8 Hz), 7.68(1H,s), 7.85(1H,d,J=4.4 Hz), 7.98(1H,d,J=7.6Hz), 8.67(1H,d,J=7.6 Hz), 11.76(1H, s). MS (FAB) m/z: 529(M+H)⁺.

Example 154(1R*,2S*,4S*)—N²-[(5-Chloroindol-2-yl)carbonyl]-4-[N-(2-methoxyethyl)carbamoyl)-N¹-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1510]

[1511] The title compound was obtained from(1R*,2S*,4S*)-4-carboxy-N²-[(5-chloroindol-2-yl)carbonyl]-N¹-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminelithium salt and 2-methoxyethylamine in a similar manner to Example 134.

[1512]¹H-NMR (DMSO-d₆) δ: 1.50-1.80(4H,m), 1.95-2.05(2H,m),2.85-2.95(4H,m), 3.10-3.40(10H,m), 3.40-3.70(2H,m), 4.15-4.70(4H,m),7.02(1H,s), 7.16(1H,d,J=8.8 Hz), 7.41(1H,d,J=8.8 Hz), 7.69(1H,s),7.95-8.05(1H,m), 8.08(1H,d,J=7.6 Hz), 8.67(1H,d,J=7.8 Hz),11.20-11.90(2H,m). MS (FAB) m/z: 573(M+H)⁺.

Example 155(1R*,2S*,4S*)—N²-[(5-Chloroindol-2-yl)carbonyl]-4-(N-isopropylcarbamoyl)-N¹-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1513]

[1514] The title compound was obtained from(1R*,2S*,4S*)-4-carboxy-N²-[(5-chloroindol-2-yl)carbonyl]-N¹-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminelithium salt and isopropylamine in a similar manner to Example 134.

[1515]¹H-NMR (DMSO-d₆) δ: 1.00-1.10(6H,m), 1.50-1.80(4H,m),1.95-2.05(2H,m), 2.35-2.45(1H,m), 2.91(3H,s), 3.15-3.25(2H,m),3.45-3.70(2H,m), 3.80-3.90(1H,m), 4.20-4.70(4H,m), 7.02(1H,d,J=1.5 Hz),7.16(1H,dd,J=8.8,2.2 Hz), 7.41(1H,d,J=8.8 Hz), 7.68(1H,d,J=1.7 Hz),7.76(1H,d,J=7.6 Hz), 8.04(1H,d,J=8.8 Hz), 8.68(1H,d,J=7.8 Hz),11.39(1H,br), 11.76(1H,s). MS (FAB) m/z: 557(M+H)⁺.

Example 156(1R*,2S*,4S*)—N²-[(5-Chloroindol-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-N¹-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1516]

[1517] The title compound was obtained from(1R*,2S*,4S*)-4-carboxy-N²-[(5-chloroindol-2-yl)carbonyl]-N¹-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminelithium salt and dimethylamine hydrochloride in a similar manner toExample 134.

[1518]¹H-NMR (DMSO-d₆) δ: 1.40-1.60(2H,m), 1.65-1.80(2H,m)1.95-2.10(2H,m), 2.84(3H,s), 2.90-3.05(1H,m), 2.92(3H,s), 3.06(3H,s),3.15-3.75(4H,m), 4.25-4.75(4H,m), 7.02(1H,d,J=1.5 Hz),7.15(1H,dd,J=8.8,2.1 Hz), 7.41(1H,d,J=8.8 Hz), 7.69(1H,d,J=2.1 Hz),8.05(1H,d, J=7.7 Hz), 8.63(1H,d,J=7.7 Hz), 11.20(1H,br), 11.79(1H,s). MS(FAB) m/z: 543(M+H)⁺.

Example 157(1S,2R,4R)—N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-(piperidin-1-yl)carbonyl-1,2-cyclohexanediaminehydrochloride

[1519]

[1520](1S,2R,4R)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-methoxycarbonyl-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(200 mg) was dissolved in tetrahydrofuran (5 ml) and water (0.6 ml), andlithium hydroxide (12 mg) was added to stir the mixture at roomtemperature. After 3 hours, the reaction was stopped, the solvent wasconcentrated under reduced pressure, and the residue was then dissolvedin N,N-dimethylformamide (10 ml), to which piperidine (65 mg),1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (110 mg),1-hydroxybenzotriazole (77 mg) and diisopropylethylamine (390 mg) wereadded, and the mixture was stirred at room temperature for 3 days. Thesolvent was distilled off under reduced pressure, dichloromethane wasadded to the residue, and the resultant mixture was washed with asaturated aqueous solution of sodium hydrogencarbonate. The resultantorganic layer was dried over anhydrous magnesium sulfate. The solventwas distilled off under reduced pressure, and the resultant residue waspurified by column chromatography on silica gel(methanol:dichloromethane=1:10) to obtain a product (132 mg) in a freeform. This product was dissolved in methanol, to which 1N ethanolsolution (230 μl) of hydrochloric acid was added. The mixture was driedto solid. Ether was added to the residue to solidify it. This solid wascollected by filtration to obtain the title compound (127 mg) as acolorless solid.

[1521]¹H-NMR (CD₃OD) δ: 1.55-2.10(12H,m), 3.06(3H,s), 3.07-3.16(3H,m),3.59-3.70(7H,m), 4.35(1H,br.s), 4.61(2H,br.s), 7.13-7.21(2H,m),7.41(1H,d,J=8.8 Hz), 7.60(1H,s),7.86(0.5H,d,J=7.6 Hz), 8.84(0.5H,d,J=7.6Hz). MS (FAB) m/z: 583(M+H)⁺.

Example 158(1S,2R,4S)—N¹-[(5-Fluoroindol-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1522]

[1523](1S,2R,4S)-4-Ethoxycarbonyl-N¹-[(5-fluoroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminewas hydrolyzed and then subjected to a condensation reaction withdimethylamine hydrochloride in a similar manner to Example 157 to obtainthe title compound.

[1524]¹H-NMR (DMSO-d₆) δ: 1.48-2.00(6H,m), 2.60-3.30(5H,m), 2.80(3H,s),2.91(3H,s), 2.98(3H,s), 3.70-4.68(4H,m), 7.00-7.06(2H,m),7.37-7.42(2H,m), 8.36-8.41(2H,m), 11.69(1H,s). MS (FAB) m/z: 527(M+H)⁺.

Example 159(1S,2R,4S)—N¹-[(5-Fluoroindol-2-yl)carbonyl]-4-(N-methylcarbamoyl)-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1525]

[1526](1S,2R,4S)-4-Ethoxycarbonyl-N¹-[(5-fluoroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexahediaminewas hydrolyzed and then subjected to a condensation reaction withmonomethylamine hydrochloride in a similar manner to Example 157 toobtain the title compound.

[1527]¹H-NMR (DMSO-d₆) δ: 1.57-2.04(6H,m), 2.33-2.41(1H,m), 2.55(3H,s),2.92(3H,s), 3.17-3.7,1(4H,m), 4.13-4.14(1H,m), 4.46(2H,br.s),4.69-4.73(1H,m), 7.00-7.05(2H,m), 7.38-7.42(2H,m), 7.77(1H,s),8.09-8.15(1H,m), 8.39(1H,d,J=7.6 Hz), 11.70(1H,s). MS (FAB) m/z:513(M+H)⁺.

Example 160(1S,2R,4S)-4-[N-(tert-Butyl)carbamoyl]-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1528]

[1529](1S,2R,4S)—N²-(tert-Butoxycarbonyl)-4-[N-(tert-butyl)carbamoyl]-N¹-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediaminewas treated with a 4N dioxane solution of hydrochloric acid and thencondensed with lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in asimilar manner to Example 118 to obtain the title compound.

[1530]¹H-NMR (DMSO-d₆) δ: 1.23(9H,s), 1.50-2.00(6H,m), 2.30-2.50(1H.,m),2.93(3H,s), 3.10-3.80(4H,m), 4.05-4.80(4H,m), 7.03(1H,d,J=1.5 Hz),7.16(1H,dd,J=8.8,2.0 Hz), 7.35-7.45(2H,m), 7.68(1H,d,J=2.0 Hz),7.90-8.10(1H,m), 8.42(1H,d,J=8.1 Hz), 11.30-11.45(1H,m), 11.79(1H,s). MS(FAB) m/z: 571(M+H)⁺.

Example 161(1S,2R,4S)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-[[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1531]

[1532] 1) (3R)-1-Benzyl-3-(tert-butyldiphenyl-silyloxy)pyrrolidine (1.18g) was dissolved in methanol (12 ml), 1N hydrochloric acid (240 μl) andpalladium hydride (221 mg) were added, and hydrogen was introduced toconduct catalytic reduction under normal pressure at room temperaturefor 4.5 hours. The catalyst was removed by filtration, and the filtratewas concentrated to solid under reduced pressure to obtain crude(3R)-3-(tert-butyldiphenyl-silyloxy)pyrrolidine hydrochloride (984 mg).

[1533] The thus-obtained product (249 mg),(1S,2R,4S)-4-carboxy-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(295 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(126 mg) and 1-hydroxybenzotriazole (87 mg) were dissolved inN,N-dimethylformamide (10 ml). Diisopropylethylamine (450 μl) was addeddropwise to the solution under ice cooling, and the mixture was stirredat room temperature for 12 hours. The solvent was distilled off underreduced pressure, dichloromethane and a saturated aqueous solution ofsodium hydrogencarbonate were added to the residue to conduct liquidseparation. The resultant organic layer was dried over anhydrous sodiumsulfate, and the solvent was distilled off under reduced pressure. Theresidue was subjected to flash column chromatography on silica gel(methanol:dichloromethane=3:97) to obtain(1S,2R,4S)-4-[[(3R)-3-(tert-butyldiphenylsilyloxy)pyrrolidin-1-yl]carbonyl]-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(248 mg) as a pale yellow amorphous substance.

[1534]¹H-NMR (CDCl₃) δ: 1.06(9H,s), 1.50-1.60(1H,m), 1.75-2.10(5H,m),2.20-2.50(2H,m), 2.54(3H,d,J=2.8 Hz), 2.60-3.00(5H,m), 3.30-3.80(6H,m),4.10-4.20(1H,m), 4.40-4.70(2H,m), 6.85(1H,s), 7.15-7.25(1H,m),7.30-7.50(8H,m), 7.60-7.70(5H,m), 7.90-8.00(1H,m), 9.38(1H,s). MS (FAB)m/z: 823(M+H)⁺.

[1535] 2) The above product (240 mg) was dissolved in pyridine (10 ml),and hydrogen fluoride-pyridine complex (3.0 ml) was added dropwise underice cooling to stir the mixture at 0° C. for 4.5 hours. Ethyl acetate(80 ml) was added to the reaction mixture under ice cooling to diluteit. The diluted reaction mixture was poured into ice. After sodiumhydrogencarbonate was added to this solution to alkalify it, liquidseparation was conducted. The resultant organic layer was dried overanhydrous sodium sulfate. The solvent was distilled under reducedpressure, and the residue was purified by column chromatography onsilica gel (methanol:dichloromethane=1:19→1:9). The resultant crudepurified product was dissolved in dichloromethane and methanol, to which1N ethanol solution (225 μl) of hydrochloric acid was added, then dry itonce. Methanol and ether were added to the residue to solidify it,thereby obtaining the hydrochloride (114 mg) of the title compound ascolorless powder.

[1536] 1H-NMR (DMSO-d₆) δ: 1.50-1.60(1H,m), 1.70-2.10(6H,m),2.75-2.85(1H,m), 2.92(3H,s), 3.10-3.80(8H,m), 4.10-5.10(6H,m),7.05(1H,d,J=1.7 Hz), 7.16(1H,dd,J=8.8,1.7 Hz), 7.42(1H,d,J=8.8 Hz),7.68(1H,s), 8.30-8.45(2H,m), 11.10-11.40(1H,m), 11.78(1H,s). MS (FAB)m/z: 585(M+H)⁺.

Example 162(1S,2R,4S)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-[(3-hydroxyazetidin-1-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1537]

[1538] 1) After 1-benzhydryl-3-(tert-butyldiphenyl-silyloxy)azetidinewas catalytically reduced in the same manner as in the step 1) ofExample 161 to obtain 3-(tert-butyldiphenylsilyloxy)azetidinehydrochloride, the resultant was condensed with(1S,2R,4S)-4-carboxy-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamineto obtain(1S,2R,4S)-4-[[3-(tert-butyldiphenylsilyloxy)-azetidin-1-yl]carbonyl]-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine.

[1539]¹H-NMR (CDCl₃) δ: 1.07(9H,s),1.50-2.50(5H,m), 2.55(3H,d,J=2.0 Hz),2.80-3.00(6H,m), 3.70-3.80(2H,m), 3.90-4.30(5H,m), 4.55-4.65(2H,m),6.84(1H,br), 7.15-7.25(1H,m), 7.30-7.50(8H,m), 7.60-7.70(5H,m),7.90-8.10(1H,m), 9.30(1H,br). MS (FAB) m/z: 809(M+H)⁺.

[1540] 2) The title compound was obtained from the above-describedproduct in the same manner as in the step 2) of Example 161.

[1541]¹H-NMR (DMSO-d₆) δ: 1.45-1.55(1H,m), 1.60-2.10(5H,m),2.55-2.65(1H,m), 2.91(3H,s), 3.10-3.90(6H,m), 4.00-4.30(3H,m),4.40-5.80(5H,m), 7.06(1H,d,J=1.5 Hz), 7.16(1H,dd,J=8.8,2.2 Hz),7.42(1H,d,J=8.8 Hz), 7.69(1H,d,J=1.7 Hz), 8.30-8.45(2H,m),11.40-11.60(1H,m), 11.80(1H,s). MS (FAB) m/z: 571(M+H)⁺.

Example 163(1S,2R,4S)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-N²-[5-(1,1-dimethyl-2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[1542]

[1543] 1)(1S,2R,4S)—N²-(tert-Butoxycarbonyl)-N¹-[(5-chloroindol-2-yl)carbonyl]-4-(N,N-dimethyl-carbamoyl)-1,2-cyclohexanediamine(200 mg) was dissolved in dichloromethane (6 ml), trifluoroacetic acid(2 ml) was added, and the mixture was stirred at room temperature for2.5 hours. The solvent was distilled off under reduced pressure toobtain(1S,2R,4S)—N¹-[(5-chloroindol-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediaminetrifluoroacetate.

[1544] The trifluoroacetate, lithium5-[1,1-dimethyl-2-(tert-butyldiphenylsilyloxy)ethyl]-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxylate(324 mg), N-methylmorpholine (143 μl) and 1-hydroxy-benzotriazolemonohydrate (86 mg) were dissolved in N,N-dimethylformamide (5 ml), andthe solution was reacted with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (108 mg) asa condensing agent, thereby obtaining(1S,2R,4S)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-N²-5-[1,1-dimethyl-2-(tert-butyldiphenylsilyloxy)ethyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(363 mg) as an amorphous solid.

[1545]¹H-NMR (CDCl₃) δ: 1.07(s,9H), 1.66(m,2H), 1.77(m,1H), 1.84(m,1H),2.04(m,1H), 2.23(m,1H), 2.34(m,1H), 2.84-3.06(8H), 2.97(s,3H),3.10(s,3H), 3.58(m,1H), 3.62(s,2H), 3.98(s,1H), 4.03(s,2H), 4.17(m,1H),4.63(m,1H), 6.84(s,1H), 7.20(dd,1H,J=8.8,2.0 Hz), 7.33(d,1H,J=8.8 Hz),7.39-7.66(12H), 7.89(1H,d,J=5.9 Hz), 9.34(1H,s).

[1546] 2) The title compound was obtained from the above product in thesame manner as in the step 3) of Example 69.

[1547]¹H-NMR (DMSO-d₆) δ: 1.54(1H,m), 1.74(3H,m), 1.97(2H,m),2.76(1H,m), 2.80(3H,s), 2.91(3H,s), 2.98(3H,s), 3.00-3.76(3H),3.04(2H,m), 3.18(2H,m), 3.49(1H,m), 3.68(1H,m), 4.12(1H,br,J=3.6 Hz),4.43(1H,m), 4.59(1H,d,J=3.6 Hz), 4.67(1H,m), 7.05(1H,s), 7.17(1H,d,J=8.8Hz), 7.41(1H,d,J=8.8 Hz), 11.78(1H,s), 7.68(1H,s), 8.38(1H,s),8.40(1H,s), 11.35(1H,br.s). MS (ESI) m/z: 601(M+H)⁺.

Example 164 (±)-cis-N¹ (orN²)-[(5-Chloroindol-2-yl)carbonyl]-4,4-dimethoxy-N²(orN¹)-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[1548] The title compound was obtained from (±)-cis-N¹(orN2)-[(5-chloroindol-2-yl)carbonyl]-4,4-dimethoxy-1,2-cyclohexanediamineand lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in asimilar manner to Example 2.

[1549]¹H-NMR (CDCl₃) δ: 2.13(1H,m), 2.23(1H,m), 2.42(1H,m), 2.46(3H,s),2.72(1H,m), 2.84(1H,m),3.21(3H,s), 3.24(3H,s), 3.49(1H,s),3.58(1H,d,J=15.6 Hz), 3.71(1H,d,J=15.6 Hz), 3.89(1H,m),4.28(1H,m),6.85(1H,d,J=2.0 Hz), 7.19(1H,dd,J=8.5,2.0 Hz), 7.30(1H,d,J=8.5 Hz),7.62(1H,s),9.21(1H,s).

Example 165 (±)-cis-N¹(or N²)-[(5-Chloroindol-2-yl)carbonyl]-N² (orN¹)-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-oxo-1,2-cyclohexanediamine

[1550] (±)-cis-N¹(orN²)-[(5-Chloroindol-2-yl)carbonyl]-4,4-dimethoxy-N²(orN¹)-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(100 mg) was dissolved in chloroform (2 ml), and trifluoroacetic acid(0.5 ml) and water (0.5 ml) were added to stir the mixture at roomtemperature for 3.5 hours. A saturated aqueous solution of sodiumhydrogencarbonate was added to the reaction mixture to conductextraction with ethyl acetate. The resultant organic layer was washedwith saturated saline and dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure, and the resultantresidue was purified by preparative thin-layer chromatography on silicagel (dichloromethane:methanol=19:1). The thus-obtained white solid wasdissolved in methanol (4 ml), to which a 1N ethanol solution (0.38 ml)of hydrochloric acid was added. The solvent was distilled off underreduced pressure to obtain the title compound (35 mg) as white powder.

[1551]¹H-NMR (DMSO-d₆) δ: 1.86(1H,m), 2.09(1H,m), 2.30(1H,m),2.54(1H,m), 2.87(3H,s), 2.96(1H,t,J=13.0 Hz), 3.08(2H,m), 3.35(3H,m),4.03(2H,m), 4.56(2H,m), 7.03(1H,s), 7.15(1H,d,J=8.8 Hz), 7.38(1H,d,J=8.8Hz), 7.69(1H,s), 8.43(1H,d,J=8.8 Hz), 8.91(1H,d,J=8.8 Hz), 11.75(1H,s).

Example 166 (±)-cis-N¹(orN²)-[(5-Chloroindol-2-yl)carbonyl]-4-hydroxyimino-N² (orN¹)-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[1552] (±)-cis-N¹ (or N²)-[(5-Chloroindol-2-yl)carbonyl]-N² (orN¹)-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-oxo-1,2-cyclohexanediamine(133 mg) was dissolved in a mixed solvent of pyridine (8 ml) andmethanol (8 ml), and hydroxylamine hydrochloride (30 mg) was added tostir the mixture at room temperature for 3 days. The reaction mixturewas concentrated, and water was added to the residue to conductextraction with ethyl acetate. The resultant organic layer was washedwith saturated saline and dried over anhydrous magnesium sulfate. Thesolvent was distilled off under reduced pressure, and the resultantresidue was purified by column chromatography on silica gel(dichloromethane:methanol=97:3→17:3) to obtain the title compound (131mg) as a colorless solid.

[1553]¹H-NMR (CDCl₃) δ: 1.43-1.86(3H), 2.01(1H,m), 2.28(1H,m),2.45(3H,s), 2.51(1H,m), 2.69(1H,m), 2.82(3H,m), 3.86-3.43(2H,m),4.20(2H,m), 6.85(1H,s), 7.16-7.13(1H,m), 7.22(1H,m), 7.46,7.50(total1H,s), 7.56-7.64(2H), 9.59,9.62(total 1H,s).

Example 167 (±)-cis-N¹ (orN²)-[(5-Chloroindol-2-yl)carbonyl]-4,4-(1,2-ethylenedioxy)-N² (orN¹)-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[1554] The title compound was obtained from (±)-cis-N¹(orN²)-[(5-chloroindol-2-yl)carbonyl]-4,4-(1,2-ethylenedioxy)-1,2-cyclohexanediamineand lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in asimilar manner to Example 2.

[1555]¹H-NMR (CDCl₃) δ: 1.69-1.87(6H,m), 2.31(1H,m), 2.47(3H,s),2.73(1H,m), 2.86(2H,m), 3.58(1H,d,J=15.4 Hz), 3.72(1H,d,J=15.4 Hz),3.91(1H,m),3.99(4H,s), 4.38(1H,m), 6.86(1H,d,J=2.0 Hz),7.19(1H,dd,J=8.8,2.0 Hz), 7.30(1H,d,J=8.8 Hz), 7.38(1H,d,J=7.3 Hz),7.62(1H,d,J=2.0 Hz), 9.15(1H,s).

Example 168 (±)-cis-N²(orN¹)-[(5-Chloroindol-2-yl)carbonyl]-4,4-(1,2-ethylenedioxy)-N¹ (orN²)-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[1556] The title compound was obtained from (±)-cis-N²(orN¹)-[(5-chloroindol-2-yl)carbonyl]-4,4-(1,2-ethylenedioxy)-1,2-cyclohexanediamineand lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in asimilar manner to Example 2.

[1557]¹H-NMR (CDCl₃) δ: 1.71-1.93(5H,m), 2.07(1H,m), 2.45(1H,m),2.47(3H,s), 2.72(1H,m), 2.86(2H,m), 3.59(1H,d,J=15.4 Hz),3.72(1H,d,J=15.4 Hz), 3.98(4H,s), 4.05(1H,m), 4.16(1H,m), 4.25(1H,m),6.85(1H, s) 7.18(1H,dd,J=8.8,2.0 Hz), 7.34(1H,d,J=8.8 Hz),7.39(1H,d,J=7.1 Hz), 7.61(1H,s), 9.47(1H,s).

Example 169 (±)-cis-N¹(orN²)-[(5-Chloroindol-2-yl)carbonyl]-4-methoxyimino-N²(orN¹)-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[1558] 1)(±)-cis-N¹,N²-bis(tert-Butoxycarbonyl)-4-methoxyimino-1,2-cyclohexanediamine(2.21 g) was dissolved in dichloromethane (30 ml), and trifluoroaceticacid (6 ml) was added to stir the mixture at room temperature for 1.5hours. The reaction mixture was concentrated, dried with a vacuum pumpand then dissolved in N,N-dimethylformamide (20 ml), to which5-chloroindole-2-carboxylic acid (500 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (593 mg),1-hydroxybenzotriazole monohydrate (473 mg) and N-methylmorpholine (2.8ml) were added. The mixture was stirred at room temperature for 10hours. Additionally, 5-chloroindole-2-carboxylic acid (242 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (237 mg) and1-hydroxybenzotriazole monohydrate (189 mg) were added to stir themixture for 4 hours. A saturated aqueous solution of sodiumhydrogencarbonate was added to the reaction mixture to conductextraction with ethyl acetate and with a mixed solvent of ethyl acetateand tetrahydrofuran. The resultant organic layer was washed withsaturated saline and dried over anhydrous sodium sulfate. The solventwas distilled off under reduced pressure, and the resultant residue waspurified by column chromatography on silica gel(dichloromethane:methanol=97:3→4:1) to obtain (±)-cis-N¹(orN²)-[(5-chloroindol-2-yl)carbonyl]-4-methoxyimino-1,2-cyclohexanediamine(368 mg) and (+)-cis-N² (orN¹)-[(5-chloroindol-2-yl)carbonyl]-4-methoxyimino-1,2-cyclohexanediamine(300 mg).

[1559] 2) The title compound (mixture of syn and anti isomers at themethoxyimino group portion) from the above-obtained (±)-cis-N¹ (orN²)-[(5-chloroindol-2-yl)carbonyl]-4-methoxyimino-1,2-cyclohexanediamineand lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxylate in asimilar manner to Example 2.

[1560]¹H-NMR (CDCl₃) δ: 1.84-2.00(3H,m), 2.26-2.56(3H,m), 2.46(3H,s),2.81(4H,m), 3.57(1H,q,J=15.4 Hz), 3.70(1H,q,J=15.4 Hz), 3.84,3.85(total3H,s), 4.11(1H,m), 4.28(1H,m), 6.84(1H,s), 7.17(1H,d,J=8.8 Hz),7.27(1H,d,J=8.8 Hz), 7.46(2H,m), 7.56(1H,m), 9.42,9.55(total 1H,s).

Example 170 (1R*,2S*)—N¹ (orN²)-[(5-Chloroindol-2-yl)carbonyl]-4-hydroxy-N² (orN¹)-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(Stereoisomer A)

[1561] 1)(1R*,2S*)-N¹,N²-Bis(tert-butoxycarbonyl)-4-(tert-butyldiphenylsilyloxy)-1,2-cyclohexanediamine(Stereoisomer A) was subjected to de(tert-butoxycarbonylation) in thesame manner as in the step 1) of Example 169 and reacted with5-chloroindole-2-carboxylic acid, thereby obtaining(1R*,2S*)-4-(tert-butyldiphenylsilyloxy)-N¹ (orN²)-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexane-diamine (StereoisomerA) and (1R*,2S*)-4-(tert-butyldiphenylsilyloxy)-N² (orN¹)-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine (StereoisomerA).

[1562] 2) (1R*,2S*)-4-(tert-Butyldiphenylsilyloxy)-N¹ (orN²)-[(5-chloroindol-2-yl)carbonyl]-N²(orN¹)-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(Stereoisomer A) was obtained from(1R*,2S*)-4-(tert-butyldiphenyl-silyloxy)-N¹ (orN²)-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine (StereoisomerA) obtained by the above reaction and lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxylate in asimilar manner to Example 2.

[1563]¹H-NMR (CDCl₃) δ: 1.06(9H,s), 1.58(1H,m), 1.87(1H,m), 2.21(1H,m),2.46(3H,s), 2.51(2H,d,J=7.6 Hz), 2.72(1H,m), 3.56(1H,s),3.57(1H,d,J=15.3 Hz), 3.72(1H,d,J=15.3 Hz), 3.76(1H,m), 3.92(1H,m),6.78(1H,s), 7.17(1H,dd,J=2.0,8.8 Hz), 7.40(7H,m), 7.59(1H,s),7.66(6H,m), 9.30(1H,s).

[1564] 3) The title compound was obtained from the compound obtained bythe above-described reaction in the same manner as in the step 1) ofExample 69.

[1565]¹H-NMR (DMSO-d₆) δ: 1.28(2H,m), 1.45-1.64(2H,m) 1.86(1H,d,J=9.0Hz), 2.02(1H,m), 2.33(3H,s), 2.69(2H,m), 2.77(2H,m), 3.54(1H,d,J=15.6Hz), 3.62(1H,d,J=15.6 Hz), 3.99(2H,m), 4.78(1H,d,J=4.2 Hz), 7.00(1H,s),7.14(1H,dd,J=2.0,8.8 Hz), 7.38(1H,d,J=8.8 Hz), 7.66(1H,s),8.20(1H,d,J=7.8 Hz), 8.54(1H,d,J=7.8 Hz), 11.69(1H,s).

Example 171 (1R*,2S*)—N² (orN¹)-[(5-Chloroindol-2-yl)carbonyl]-4-hydroxy-N¹ (orN²)-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(Stereoisomer B)

[1566] 1)(1R*,2S*)-4-Acetoxy-N¹,N²-bis(tert-butoxycarbonyl)-1,2-cyclohexanediamine(Stereoisomer B) was subjected to de(tert-butoxycarbonylation) in thesame manner as in the step 1) of Example 169 and reacted with5-chloroindole-2-carboxylic acid. The reaction mixture was subjected tochromatography on silica gel, thereby obtaining (1R*,2S*)-4-acetoxy-N¹(or N²)-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine(Stereoisomer B) and (1R*,2S*)-4-acetoxy-N² (orN¹)-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine (StereoisomerB).

[1567] 2) (1R*,2S*)-4-Acetoxy-N²(orN¹)-[(5-chloroindol-2-yl)carbonyl]-N¹ (orN²)-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclobutanediamine(Stereoisomer B) was obtained from (1R*,2S*)-4-acetoxy-N²(orN¹)-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine (StereoisomerB) obtained by the above reaction and lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in asimilar manner to Example 2.

[1568]¹H-NMR (CDCl₃) δ: 1.74(2H,m), 2.09(2H,m), 2.11(3H,s), 2.29(2H,m),2.47(3H,s), 2.73(1H,m), 2.84(3H,m), 3.59(1H,d,J=15.4 Hz),3.72(1H,d,J=15.4 Hz), 3.89(1H,m), 4.41(1H,m), 5.24(1H,s), 6.87(1H,s),7.20(1H,dd,J=8.8,2.0 Hz), 7.26(1H), 7.30(1H,d,J=8.8 Hz), 7.43(1H,d,J=6.8Hz), 7.64(1H,s), 9.13(1H,s). MS (ESI) m/z: 530(M+H)⁺.

[1569] 3) The above-obtained product (82 mg) was dissolved intetrahydrofuran (2 ml)-methanol (2 ml), to which 1N lithium hydroxide(232 ml) was added, and the mixture was stirred at room temperature for4 hours. Water was added to the reaction mixture to conduct extractionwith ethyl acetate. The resultant organic layer was washed withsaturated saline and dried over anhydrous magnesium sulfate. The solventwas distilled off under reduced pressure, and the resultant residue waspurified by preparative thin-layer chromatography(dichloromethane:methanol=47:3) to obtain the title compound (53 mg) asa pale yellow solid.

[1570]¹H-NMR (CDCl₃) δ: 1.75(4H,m), 1.92(3H,m), 2.15(1H,m), 2.23(1H,m),2.46(3H,s), 2.72(1H,m), 2.85(2H,m), 3.58(1H,d,J=15.6 Hz),3.70(1H,d,J=15.6 Hz), 4.33(1H,s), 3.93(1H,m), 4.56(1H,m),6.89(1H,d,J=2.0 Hz), 7.18(1H,dd,J=8.8,2.0 Hz), 7.27(1H), 7.31(1H,d,J=8.8Hz), 7.46(1H,d,J=7.1 Hz), 7.58(1H,s), 9.16(1H,s).

Example 172 (1R*,2S*)—N¹ (orN²)-[(5-Chloroindol-2-yl)carbonyl]-4-hydroxy-4-methyl-N² (orN¹)-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(Stereoisomer A1) and (1R*,2S*)—N² (orN¹)-[(5-chloroindol-2-yl)carbonyl]-4-hydroxy-4-methyl-N¹ (orN²)-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexane-diamine(Stereoisomer A2):

[1571] The title compounds were obtained by reacting a mixture of(1R*,2S*)-N¹-[(5-chloroindol-2-yl)carbonyl]-4-hydroxy-4-methyl-1,2-cyclohexanediamine(Stereoisomer A) and(1R*,2S*)—N²-[(5-chloroindol-2-yl)carbonyl]-4-hydroxy-4-methyl-1,2-cyclohexanediamine(Stereoisomer A) with lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in asimilar manner to Example 2.

[1572] Stereoisomer A1:

[1573]¹H-NMR (DMSO-d₆) δ: 1.24(3H,s), 1.33-1.82(4H,m), 2.34(3H,s),2.67-3.64(8H,m), 4.06(2H,br), 4.67(1H,br), 7.02(1H,s), 7.13(1H,d,J=8.6Hz), 7.38(1H,d,J=8.6 Hz), 7.66(1H,d,J=2.0 Hz), 8.23(1H,br),8.59(1H,d,J=8.1 Hz), 11.73(1H,br) MS (FAB) m/z: 502(M+H)⁺.

[1574] Stereoisomer A2:

[1575]¹H-NMR (DMSO-d₆) δ: 1.25(3H,s), 1.33-1.79(4H,m), 2.33(3H,s),2.65-3.63(8H,m), 3.88-3.94(1H,m), 4.23(1H,m), 4.59(1H,br), 7.01(1H,s),7.13(1H,d, J=7.8 Hz), 7.38(1H,d,J=8.6 Hz), 7.67(1H,s), 8.29(1H,br),8.43(1H,d,J=9.3 Hz), 11.67(1H,br) MS (FAB) m/z: 502(M+H)⁺.

Example 173 (1R*,2S*)—N¹ (orN²)-[(5-Chloroindol-2-yl)carbonyl]-4-hydroxy-4-methyl-N² (orN¹)-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(Stereoisomer B)

[1576] The title compound was obtained from (1R*,2S*)—N¹ (orN²)-[(5-chloroindol-2-yl)carbonyl]-4-hydroxy-4-methyl-1,2-cyclohexanediamine(Stereoisomer B) and lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in asimilar manner to Example 2.

[1577]¹H-NMR (DMSO-d₆) δ: 1.16(3H,s), 1.24(1H,br), 1.39-1.42(1H,m),1.57-1.79(3H,m), 1.92-1.94(1H,m), 2.33(3H,s), 2.66-2.78(4H,m),3.53(1H,d,J=15.7 Hz), 3.60(1H,d,J=15.7 Hz), 4.01(1H,br), 4.32(1H,br),7.04(1H,s), 7.13(1H,dd,J=8.8,2.0 Hz), 7.37(1H,d,J=8.8 Hz),7.65(1H,d,J=2.0 Hz), 8.24(1H,d,J=8.8 Hz), 8.28(1H,d,J=9.0 Hz),11.65(1H,br) MS (FAB) m/z: 502(M+H)⁺.

Example 174(1R*,2S*)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-hydroxymethyl-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(Stereoisomer A)

[1578]

[1579] 1)(1R*,2S*)-4-(tert-Butyldiphenylsilyloxy-methyl)-N¹-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine(Stereoisomer A) was obtained from(1R*,2S*)-4-(tert-butyldiphenylsilyloxymethyl)-1,2-cyclobutanediamine(Stereoisomer A) and 5-chloroindole-2-carboxylic acid in a similarmanner to Referential Example 30.

[1580] 2)(1R*,2S*)-4-(tert-butyldiphenylsilyloxy-methyl)-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride (Stereoisomer A) was obtained from the compound obtainedabove and lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in asimilar manner to Example 2.

[1581]¹H-NMR (DMSO-d₆) δ: 1.04(9H,s), 1.23-2.07(7H,m), 2.35(3H,s),2.73-2.89(4H,m), 3.58-3.59(2H,m), 3.63(2H,br.s), 4.20(1H,m),4.31(1H,br.s), 7.16(1H,s), 7.19(1H,dd,J=8.8,1.2 Hz), 7.42-7.46(6H,m),7.63-7.65(4H,m), 7.69(1H,br.s), 7.88(1H,d,J=6.6 Hz), 7.95(1H,s),8.71(1H,d,J=8.5 Hz), 11.82(1H,s). MS (FAB) m/z: 741(M+H)⁺.

[1582] The title compound was obtained by treating the above product ina similar manner to the step 3) of Example 69.

[1583]¹H-NMR (DMSO-d₆) δ: 1.21-1.23(1H,m), 1.49-1.72(5H,m),2.00-2.04(1H,m), 2.34(3H,s), 2.67-2.69(2H,m), 2.74-2.75(2H,m),3.62(2H,s), 4.10-4.13(2H,m), 4.31(1H,br.s), 4.53(1H,m),7.17-7.20(2H,m),7.43(1H,d,J=8.6 Hz), 7.73(1H,d,J=2.0 Hz), 7.91(1H,d,J=6.9 Hz),8.64(1H,d,J=8.6 Hz), 11.83(1H,s) MS (FAB) m/z: 502(M+H)⁺.

Example 175(1R*,2R*,4S*)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-hydroxymethyl-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[1584]

[1585] The title compound was obtained by treating(1R*,2R*,4S*)—N²-(tert-butoxycarbonyl)-N¹-[(5-chloroindol-2-yl)carbonyl]-4-hydroxymethyl-1,2-cyclohexanediaminewith a saturated ethanol solution of hydrochloric acid and thencondensing it with lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in asimilar manner to Example 118.

[1586]¹H-NMR (DMSO-d₆) δ: 1.42-1.90(5H,m), 2.07-2.26(3H,m), 2.46(3H,s),2.67-2.95(4H,m), 3.55-3.80(4H,m), 3.80-3.95(1H,m), 4.13-4.25(1H,m),6.84(1H,br.s), 7.17(1H,dd,J=8.8,2.0 Hz), 7.23-7.35(2H,m),7.43(1H,d,J=7.2 Hz), 7.58(1H,br.s), 9.29(1H,s). MS (ESI) m/z: 502(M+H)⁺.

Example 176(1R,2R,4S)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-hydroxymethyl-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[1587]

[1588] The title compound was obtained by treating(1R,2R,4S)—N²-(tert-butoxycarbonyl)-N¹-[(5-chloroindol-2-yl)carbonyl]-4-hydroxymethyl-1,2-cyclohexanediaminewith a saturated ethanol solution of hydrochloric acid and thencondensing it with lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxylate in asimilar manner to Example 118.

[1589]¹H-NMR (DMSO-d₆) δ: 1.42-1.90(5H,m), 2.07-2.26(3H,m), 2.46(3H,s),2.67-2.95(4H,m), 3.55-3.80(4H,m), 3.80-3.95(1H,m), 4.13-4.25(1H,m),6.84(1H,br.s), 7.17(1H,dd,J=8.8,2.0 Hz), 7.23-7.35(2H,m),7.43(1H,d,J=7.2 Hz), 7.58(1H,br.s), 9.29(1H,s). MS (ESI) m/z: 502(M+H)⁺.

Example 177(1R*,2S*,4R*)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-(1-hydroxy-1-methylethyl)-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1590]

[1591] The title compound was obtained from(1R*,2S*,4R*)—N¹-[(5-chloroindol-2-yl)carbonyl]-4-(1-hydroxy-1-methylethyl)-1,2-cyclohexanediaminehydrochloride and lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in asimilar manner to Example 2.

[1592]¹H-NMR (CD₃OD) δ: 1.17(3H,s), 1.20(3H,s), 1.24-2.22(7H,m),3.02(3H,s), 3.18-3.41(4H,m), 3.52-3.68(2H,m), 4.08-4.21(1H,m),4.50-4.65(1H,m), 6.92(1H,br.s), 7.13-7.19(1H,m), 7.39(1H,br,J=8.0 Hz),7.84-7.93(1H,m), 8.22-8.32(1H,m). MS (FAB) m/z: 530(M+H)⁺.

Example 178(1R*,2S*,4R*)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-methoxymethyl-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[1593]

[1594] The title compound was obtained by treating(1R*,2S*,4R*)—N²-(tert-butoxycarbonyl)-N¹-[(5-chloroindol-2-yl)carbonyl]-4-methoxymethyl-1,2-cyclohexanediaminewith a saturated ethanol solution of hydrochloric acid and thencondensing it with lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxylate in asimilar manner to Example 118.

[1595]¹H-NMR (CDCl₃) δ: 1.20-1.38(1H,m), 1.50-1.67(2H,m),1.88-2.03(2H,m), 2.03-2.14(1H,m), 2.21-2.32(1H,m), 2.53(3H,s),2.75-2.95(2H,m), 3.20-3.35(2H,m), 3.37(3H,s), 3.71 and 3.78(each 1H,eachd,J=11.2 Hz), 4.04-4.13(1H,m), 4.53-4.62(1H,m), 6.85(1H,d,J=2.0 Hz),7.19(1H,dd,J=8.8,2.0 Hz), 7.33(1H,d,J=8.8 Hz), 7.54(1H,d,J=7.2 Hz),7.63(1H,d,J=2.0 Hz), 8.07(1H,d,J=5.6 Hz), 9.49(1H,br.s).

Example 179 Mixture of(1R*,2S*,4R*,5S*)—N¹-[(5-chloroindol-2-yl)carbonyl]-4,5-dihydroxy-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and(1R*,2S*,4S*,5R*)—N¹-[(5-chloroindol-2-yl)carbonyl]-4,5-dihydroxy-N²-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1596]

[1597](±)-cis-N¹-[(5-Chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-cyclohexene-1,2-diamine(2.85 g) was dissolved in a mixed solvent of tetrahydrofuran (10 ml),acetone (10 ml) and water (10 ml), and osmium tetroxide (31 mg) andN-methylmorpholine-N-oxide (1.23 g) were added to stir the mixture atroom temperature for 14 hours. Further, osmium tetroxide (16 mg) andN-methylmorpholine-N-oxide (613 mg) were added to stir the mixture at40° C. for 5 days. The reaction mixture was poured into a 10% aqueoussolution of sodium thiosulfate and extracted with ethyl acetate. Theresultant organic layer was washed with saturated saline and dried overanhydrous magnesium sulfate. The solvent was distilled off under reducedpressure, and the residue was purified by column chromatography onsilica gel (dichloromethane:methanol=49:1→17:3) to obtain a crude diolderivative (811 mg). A part (200 mg) thereof was purified by preparativethin-layer chromatography (dichloromethane:methanol=93:7) and thendissolved in methanol. A 1N ethanol solution of hydrochloric acid wasadded to the solution to obtain the title compound (811 mg).

[1598]¹H-NMR (DMSO-d₆) δ: 2.02-1.79(3H,m), 2.33(3H,s), 2.76-2.64(4H,m),3.57(4H,m), 3.82(1H,br.s), 3.96,4.13(1H,m), 4.32(1H,m),4.49,4.52(1H,each d,J=16.4 Hz), 4.66,4.67(1H,each d,J=17.4 Hz),7.02,7.06(1H,each s), 7.14(1H,m), 7.37,7.39(1H,each s),7.66,7.67(1H,each d,J=2.4 Hz), 8.18,8.28(1H,each d,J=8.5 Hz),8.33,8.41(1H,each d,J=8.8 Hz), 11.67,11.71(1H,each s).

Example 180 Mixture of(1R*,2S*,4R*,5S*)—N¹-[(5-chloroindol-2-yl)carbonyl]-4,5-diacetoxy-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamineand(1R*,2S*,4S*,5R*)—N¹-[(5-chloroindol-2-yl)carbonyl]-4,5-diacetoxy-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[1599]

[1600] A mixture (200 mg) of(1R*,2S*,4R*,5S*)—N¹-[(5-chloroindol-2-yl)carbonyl]-4,5-dihydroxy-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamineand(1R*,2S*,4S*,5R*)—N¹-[(5-chloroindol-2-yl)carbonyl]-4,5-dihydroxy-N²-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminewas dissolved in pyridine (8 ml), and acetic anhydride (745 μl) wasadded to stir the mixture at room temperature for 2 days. The reactionmixture was concentrated and purified by preparative thin-layerchromatography (dichloromethane:methanol=97:3) to obtain the titlecompound (132 mg) as a pale yellow solid. This product was dissolved inmethanol (2 ml). A 1N ethanol solution (1 ml) of hydrochloric acid wasadded to the solution, and the mixture was concentrated under reducedpressure to convert the compound into the hydrochloride.

[1601]¹H-NMR (DMSO-d₆) δ: 1.96(4H,m), 2.08(3H,s), 2.09(3H,s),2.14.(3H,s), 2.33(3H,s), 2.70(4H,m), 4.31(1H,m), 4.84(1H,m), 5.26(1H,s),7.05(1H,s), 7.15(1H,d,J=8.5 Hz), 7.38(1H,d,J=8.5 Hz), 7.68(1H,s),8.49(1H,d,J=8.8 Hz), 8.54(1H,d,J=8.8 Hz),11.71(1H,s).

Example 181(1R*,2S*,4R*,5S*)-4,5-Carbonyldioxy-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride and(1R*,2S*,4S*,5R*)-4,5-Carbonyldioxy-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-room temperature. The reaction mixture was concentrated under reducedpressure, and a saturated aqueous solution of sodium hydrogencarbonatewas added to the residue to conduct extraction with dichloromethane. Theresultant organic layer was dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure, and the residue waspurified by column chromatography on silica gel(methanol:dichloromethane=1:9) to obtain a mixture (330 mg) of(1R*,2S*,4R*,5S*)—N¹-[(5-chloroindol-2-yl)carbonyl]-4,5-dimethoxy-1,2-cyclohexanediamineand(1R*,2S*,4S*,5R*)—N¹-[(5-chloroindol-2-yl)carbonyl]-4,5-dimethoxy-1,2-cyclohexanediamineas pale yellow powder.

[1602] Products obtained from the above products and lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxylate in asimilar manner to Example 2 were separated by column chromatography onsilica gel to obtain the title compounds.

[1603] One Compound:

[1604]¹H-NMR (DMSO-d₆) δ: 1.52-1.63(1H,m), 1.85-2.20(3H,m),2.88(3H,br.s), 3.10(2H,br.s), 3.25-3.50(8H,m), 3.60-3.72(1H,br),3.75(1H,br.s), 3.95-4.10(1H,m), 4.20-4.72(3H,m), 7.02(1H,s),7.14(1H,d,J=8.8 Hz), 7.37(1H,d,J=8.8 Hz), 7.68(1H,s), 8.30(1H,d,J=8.8Hz), 8.73(1H,d,J=8.8 Hz), 11.00-11.30(1H,br), 11.74(1H,br.s). MS (FAB)m/z: 532(M+H)⁺.

[1605] The Other Compound

[1606]¹H-NMR (DMSO-d₆) δ: 1.63-1.77(1H,m), 1.82-2.02(2H,m),2.05-2.18(1H,m), 2.86(3H,br.s), 2.95-3.80(12H,m), 4.10-4.70(4H,m),7.07(1H,s), 7.14(1H,dd,J=8.8,2.0 Hz), 7.37(1H,d,J=8.8 Hz),7.67(1H,d,J=2.0 Hz), 8.45(1H,d,J=8.1 Hz), 8.57(1H,d,J=8.6 Hz),11.30-11.65(1H,br), 11.70(1H,br.s). MS (FAB) m/z: 532(M+H)⁺.

Example 184(1R*,2S*,4R*)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-methanesulfonylaminomethyl-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine

[1607]

[1608] 1)(1R*,2S*,4R*)-4-Azidomethyl-N²-(tert-butoxycarbonyl)-N¹-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine(437 mg) was dissolved in ethanol (5 ml), and a 4N dioxane solution (5ml) of hydrochloric acid was added at room temperature to stir themixture for 13 hours. The solvent was distilled off, and the residue wasdissolved in N,N-dimethylformamide (10 ml) to which triethylamine (0.7ml), lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxylate (300mg), 1-hydroxybenzotriazole monohydrate (162 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (230 mg)were added. The mixture was stirred for 13 hours, and water was added tothe reaction mixture to conduct extraction with chloroform. Theresultant organic layer was washed with a saturated aqueous solution ofsodium hydrogencarbonate and saturated saline and dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure,and the resultant residue was purified by column chromatography onsilica gel (dichloromethane:methanol=97:3) to obtain(1R*,2S*,4R*)-4-azidomethyl-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(330 mg) as a pale yellow solid.

[1609]¹H-NMR (DMSO-d₆) δ: 1.15-2.08(7H,m), 2.33(3H,s), 2.34-2.95(6H,m),3.64(2H,s), 4.05-4.17(1H,m), 4.36-4.47(1H,m), 7.02(1H,s),7.15(1H,dd,J=8.8,2.0 Hz), 7.40(1H,d,J=8.8 Hz), 7.67(1H,d,J=2.0 Hz),8.02(1H,d,J=7.6 Hz), 8.44(1H,d,J=7.6 Hz), 11.8(1H,s). 2) The compound(300 mg) obtained by the above reaction was dissolved in ethanol (8 ml),and a catalytic amount of 10% palladium on carbon was added to stir themixture at room temperature for 168 hours in a hydrogen atmosphere.Insoluble matter was filtered, and the solvent was distilled off toobtain crude(1R*,2S*,4R*)-4-aminomethyl-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(150 mg).

[1610] 3) The product described above was dissolved in chloroform (6ml), and triethylamine (0.2 ml) and methanesulfonyl chloride (0.035 ml)were added to stir the mixture for 13 hours. The reaction mixture wasconcentrated under reduced pressure, and water was added to the residueto conduct extraction with chloroform. The resultant organic layer waswashed with a saturated aqueous solution of sodium hydrogencarbonate andsaturated saline and dried over anhydrous magnesium sulfate. The solventwas distilled off under reduced pressure, and the resultant residue waspurified by column chromatography on silica gel(dichloromethane:methanol=24:1) to obtain the title compound (56 mg) asa pale yellow solid.

[1611]¹H-NMR (CDCl₃) δ: 1.18-1.34(2H,m), 1.50-1.75(4H,m),1.90-2.30(4H,m), 2.53(3H,s), 2.78-2.90(2H,m), 2.90-3.05(6H,m),3.20-3.30(1H,m), 3.68-3.81(2H,m), 3.98-4.08(1H,m), 4.54-4.62(1H,m),6.10-6.19(1H,m), 6.86(1H,s), 7.19(1H,dd,J=8.8,2.0 Hz), 7.35(1H,d,J=8.8Hz), 7.52(1H,d,J=7.6 Hz), 7.62(1H,d,J=2.0 Hz), 8.21(1H,d,J=5.6 Hz),9.89(1H,s). MS (ESI) m/z: 579(M+H)⁺.

Example 185(1R*,2S*,4R*)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-(N,N-dimethylaminomethyl)-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminetrifluoroacetate:

[1612]

[1613] The title compound was obtained from(1R*,2S*,4R*)-4-aminomethyl-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamineand formalin in a similar manner to Example 45.

[1614]¹H-NMR (DMSO-d₆) δ: 1.15-2.22(7H,m), 2.40-2.65(2H,m),2.68-2.85(6H,m), 2.92-3.08(5H,m), 3.10-3.18(2H,m), 4.08-4.20(1H,m),4.35-4.51(2H,m), 7.04(1H,s), 7.14-7.20(1H,m), 7.41(1H,d,J=8.8 Hz),7.67(1H,s), 8.25-8.42(2H,m), 9.11(1H,br.s), 9.89(1H,s). MS (ESI) m/z:529(M+H)⁺.

Example 186 (1R*,2S*)—N² (orN¹)-[(5-Chloroindol-2-yl)carbonyl]-4-[1-(ethoxycarbonyl)cyclopropan-1-yl]amino-N¹(orN²)-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(Stereoisomer A)

[1615]

[1616] The title compound was obtained from (1R*,2S*)—N² (orN¹)-[(5-chloroindol-2-yl)carbonyl]-4-[1-(ethoxycarbonyl)cyclopropan-1-yl]amino-1,2-cyclohexanediamine(Stereoisomer A) and lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in asimilar manner to Example 2.

[1617]¹H-NMR (DMSO-d₆) δ: 0.93(1H,m), 1.05-1.30(6H,m), 1.45-2.10(6H,m),2.33(3H,s), 2.65-2.85(5H,m), 3.30-3.40(1H,m), 3.54(1H,d,J=15.9 Hz),3.62(1H,d,J=15.9 Hz), 4.00-4.15(3H,m), 4.25(1H,m), 7.06(1H,s),7.14(1H,dd,J=8.8,2.0 Hz), 7.38(1H,d,J=8.8 Hz), 7.65(1H,d,J=2.0 Hz),8.28(1H,d,J=9.0 Hz), 8.32(1H,d,J=8.5 Hz), 11.67(1H,s). MS (FAB) m/z:599(M+H)⁺.

Example 187(1R*,2S*)-4-(tert-Butoxycarbonylamino)-N¹-[(5-chloroindol-2-yl)carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(Isomer B) and(1R*,2S*)-4-(tert-butoxycarbonylamino)-N²-[(5-chloroindol-2-yl)carbonyl]-N¹-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(Isomer B)

[1618]

[1619] (1R*,2S*)-4-(tert-Butoxycarbonylamino-1,2-diazidocyclohexane(Stereoisomer B) (1.79 g) was dissolved in tetrahydrofuran (36 ml), and10% palladium on carbon (0.40 g) was added to stir the mixture at roomtemperature for 20 hours in a hydrogen atmosphere. After the catalystwas removed by filtration, the filtrate was concentrated under reducedpressure, and the residue was dissolved in N,N-dimethylformamide (36ml), to which p-nitrophenyl 5-chloroindole-2-carboxylate (2.02 g) wasadded to stir the mixture for 16 hours. The reaction mixture wasconcentrated under reduced pressure, and ethyl acetate and water wereadded to the residue to collect insoluble matter by filtration. Theproduct was washed with ethyl acetate to obtain crude(1R*,2S*)-4-(tert-butoxycarbonylamino)-N¹ (orN²)-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine (Isomer B1)(1.49 g) as a colorless solid. The organic layer of the filtrate waswashed with water and dried over anhydrous sodium sulfate. The solventwas distilled off under reduced pressure, and the residue was purifiedby column chromatography on silica gel(dichloromethane:methanol=30:1→-10:1) to obtain(1R*,2S*)-4-(tert-butoxycarbonylamino)-N² (orN¹)-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine (Isomer B2)(0.37 g) as a brown amorphous solid.

[1620] One of the title compounds was obtained from the Isomer B1 andlithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylatein a similar manner to Example 2.

[1621]¹H-NMR (DMSO-d₆) δ: 1.25-1.50(1H,m), 1.37(9H,s), 1.50-1.65(1H,m),1.75-2.20(4H,m),2.37(3H,s), 2.70-3.00(4H,m), 3.60-3.80(3H,m),4.13(1H,m), 4.43(1H,m), 6.92(1H,d,J=7.1 Hz), 7.05(1H,s),7.17(1H,dd,J=8.8,2.2 Hz), 7.41(1H,d,J=8.8 Hz), 7.69(1H,s),8.15(1H,d,J=7.8 Hz), 8.37(1H,d,J=7.1 Hz), 11.78(1H,s). MS (FAB) m/z:587(M+H)⁺.

[1622] The other title compound was obtained from the Isomer B2 in thesame manner.

[1623]¹H-NMR (DMSO-d₆) δ: 1.15-1.30(1H,m), 1.35(9H,s), 1.45-1.60(1H,m),1.65-1.75(1H,m), 1.85-1.95(1H,m), 2.05-2.20(2H,m), 2.34(3H,s),2.65-2.85(4H,m), 3.55-3.70(3H,m), 4.09(1H,m),4.40(1H,m), 6.80(1H,d,J=7.3Hz), 7.15-7.25(2H,,m), 7.43(1H,d,J=8.8 Hz), 7.73(1H,d,J=2.0 Hz),8.05(1H,d,J=6.6 Hz), 8.51(1H,d,J=8.8 Hz), 11.82(1H,s). MS (FAB) m/z:587(M+H)⁺.

Example 188 (1R*,2S*)-4-Amino-N¹ (orN²)-[(5-chloroindol-2-yl)-carbonyl]-N² (orN¹)-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride (Stereoisomer B)

[1624]

[1625] (1R*,2S*)-4-(tert-Butoxycarbonylamino)-N¹ (orN²)-[(5-chloroindol-2-yl)carbonyl]-N² (orN¹)-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(Stereoisomer B) (1.11 g) was suspended in dichloromethane (20 ml), anda saturated ethanol solution (20 ml) of hydrochloric acid was added tostir the mixture at room temperature for 2 hours. The solvent wasdistilled off under reduced pressure, and the residue was purified bygel filtration (Sephadex LH-20, methanol) to obtain the title compound(1.05 g) as a yellow amorphous solid.

[1626]¹H-NMR (DMSO-d₆) δ: 1.55-1.65(1H,m), 1.75-1.90(2H,m),1.95-2.20(2H,m), 2.20-2.40(1H,m), 2.90(3H,s), 3.10-3.20(1H,m),3.20-3.50(3H,m), 3.65-3.75(1H,m), 4.10-4.20(1H,m), 4.35-4.50(1H,m),4.55-4.65(1H,m), 4.65-4.75(1H,m), 7.07(1H,s), 7.17(1H,dd,J=8.8,2.0 Hz),7.42(1H,d,J=8.8 Hz), 7.69(1H,s), 8.05-8.30(3H,br), 8.40-8.50(2H,m),11.70-11.90(2H,m). MS (FAB) m/z: 487(M+H)⁺.

Example 189 (1R*,2S*)—N¹ (orN²)-[(5-Chloroindol-2-yl)carbonyl]-4-methanesulfonylamino-N² (orN¹)-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(Stereoisomer B)

[1627]

[1628] (1R*,2S*)-4-Amino-N¹ (or N²)-[(5-chloroindol-2-yl)carbonyl]-N²(orN¹)-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride (Stereoisomer B) (0.20 g) was suspended in dichloromethane(7 ml), and triethylamine (0.16 ml) and methanesulfonyl chloride (28 μl)were added to stir the mixture at room temperature for 20 hours. Afterthe reaction mixture was diluted with dichloromethane, it was washedwith an aqueous solution of sodium hydroxide and dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure,and the residue was purified by column chromatography on silica gel(dichloromethane:methanol=30:1→15:1) to obtain the title compound (67.9mg) as a colorless amorphous solid.

[1629]¹H-NMR (DMSO-d₆) δ: 1.40-1.55(1H,m), 1.65-1.85(2H,m),1.90-2.05(2H,m), 2.15-2.25(1H,m), 2.41(3H,s), 2.75-2.95(4H,m),2.92(3H,s), 3.55-3.80(3H,m), 4.10-4.20(1H,m), 4.45-4.55(1H,m),7.08(1H,s), 7.15-7.20(2H,m), 7.41(1H,d,J=8.8 Hz), 7.69(1H,s),8.27(1H,d,J=7.3 Hz), 8.33(1H,d,J=8.1 Hz), 11.77(1H,s). MS (FAB) m/z:565[(M+H)⁺.

Example 190 (1R*,2S*)-4-Acetylamino-N¹ (orN²)-[(5-chloroindol-2-yl)carbonyl]-N² (orN¹)-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(Stereoisomer B)

[1630]

[1631] (1R*,2S*)-4-Amino-N¹ (or N²)-[(5-chloroindol-2-yl)carbonyl]-N²(orN¹)-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride (Stereoisomer B) (0.20 g) was suspended in dichloromethane(7 ml), and triethylamine (0.16 ml) and acetic anhydride (34 μl) wereadded to stir the mixture at room temperature for 20 hours.Dichloromethane and an aqueous solution of sodium hydroxide were addedto the reaction mixture to separate insoluble matter by filtration. Theorganic layer of the filtrate was separated and dried over anhydroussodium sulfate, and the solvent was then distilled off under reducedpressure. The residue was purified by column chromatography on silicagel (dichloromethane:methanol=15:1→-10:1) to obtain the title compound(0.12 g) as a colorless solid.

[1632]¹H-NMR (DMSO-d₆) δ: 1.35-1.50(1H,m), 1.55-1.70(1H,m) 1.80(3H,s),1.80-2.05(3H,m), 2.05-2.20(1H,m), 2.47(3H,s), 2.80-3.00(4H,m),3.75-4.00(3H,m), 4.15-4.30(1H,m), 4.45-4.55(1H,m), 7.07(1H,s),7.17(1H,dd,J=8.8,1.0 Hz), 7.41(1H,d,J=8.8 Hz), 7.69(1H,s),7.89(1H,d,J=7.3 Hz), 8.24(1H,d,J=8.1 Hz), 8.31(1H,d,J=7.3 Hz),11.77(1H,s). MS (FAB) m/z: 528(M+H)⁺.

Example 191(1S,2R,4S)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-(N-methoxy-N-methylcarbamoyl)-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1633]

[1634](1S,2R,4S)-4-Carboxy-N-¹-[(5-chloroindol-2-yl)-carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine(250 mg) was dissolved in N,N-dimethylformamide (5 ml), andN,O-dimethylhydroxylamine hydrochloride (142 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (111 mg),1-hydroxybenzotriazole monohydrate (89 mg) and N-methylmorpholine (213ml) were added to stir the mixture at room temperature for 19 hours.After the reaction mixture was concentrated, an aqueous solution ofsodium hydrogencarbonate was added to the residue to conduct extractionwith ethyl acetate. After the resultant organic layer was washed withsaturated saline and dried over anhydrous sodium sulfate, the solventwas distilled off under reduced pressure. The residue was purified bycolumn chromatography on silica gel(dichloromethane:methanol=47:3→-23:2) to obtain a colorless amorphoussolid (179 mg). This prodcut was dissolved in methanol-tetrahydrofuran,and 1N ethanol solution (960 ml) of hydrochloric acid was added toobtain the title compound.

[1635]¹H-NMR (DMSO-d₆) δ: 1.57-1.91(4H,m), 1.96-2.00(1H,m),2.10-2.21(1H,m), 2.92(3H,s), 2.93-3.03(2H,m), 3.08(3H,s),3.10-3.28(2H,m), 4.16-4.19(1H,m), 4.50-4.52(1H,m), 4.69(1H,br.s),7.06(s,1H), 7.17(1H,dd,J=1.5,8.8 Hz), 7.42(1H,d,J=8.8 Hz), 7.70(1H,s),8.33(1H,br.s), 8.41(1H,d,J=7.8 Hz), 11.81(1H,br.s). MS (ESI) m/z:559(M+H)⁺.

Example 192(1S,2R,4S)—N¹-[(5-Chloroindol-2-yl)carbonyl]-4-(N²,N²-dimethylcarbamoyl)-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1636]

[1637] The title compound was obtained from(1S,2R,4S)-4-carboxy-N¹-[(5-chloroindol-2-yl)-carbonyl]-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamineand N,N-dimethylhydrazine in a similar manner to Example 134.

[1638]¹H-NMR (DMSO-d₆) δ: 1.49-1.54(1H,m), 1.76-1.81(2H,m),1.89-1.93(2H,m), 2.07-2.17(1H,m), 2.33-3.60(14H,m), 4.15-4.19(1H,m),4.40-4.47(2H,m), 4.70-4.72(1H,m), 7.04(1H,s), 7.17(1H,dd,J=2.0,8.5 Hz),7.42(1H,d,J=8.5 Hz), 7.70(1H,s), 8.17-8.22(1H,m), 8.41-8.43(1H,m),11.80(1H,br.s). MS (ESI) m/z: 558(M+H)⁺.

Example 193(1S,2R,4S)—N¹-[(6-Chloroquinolin-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1639]

[1640](1S,2R,4S)—N²-(tert-Butoxycarbonyl)-N¹-[(6-chloroquinolin-2-yl)carbonyl]-4-(N,N-dimethyl-carbamoyl)-1,2-cyclohexanediaminewas treated with a saturated ethanol solution of hydrochloric acid andthen condensed with lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in asimilar manner to Example 118 to obtain the title compound.

[1641]¹H-NMR (DMSO-d₆) δ: 1.45-1.60(1H,m), 1.75-1.90(3H,m),1.90-2.00(1H,m), 2.00-2.20(1H,m), 2.80(3H,s), 2.90(3H,s), 2.99(3H,s),3.10-3.30(5H,m), 3.56(1H,br), 4.10-4.20(1H,m), 4.40-4.70(2H,m),7.88(2H,s), 8.15(1H,d,J=8.6 Hz), 8.22(1H,s), 8.52(1H,d,J=8.6 Hz),8.72(1H,d,J=8.3 Hz), 8.89(1H,d,J=8.3 Hz). MS (FAB) m/z: 555(M+H)⁺.

Example 194(1S,2R,4S)—N¹-[(5-Chloro-4-fluoroindol-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1642]

[1643] 1)(1S,2R,4S)—N²-(tert-Butoxycarbonyl)-N¹-[(6-chloro-4-fluoroindol-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediaminewas obtained from(1S,2R,4S)—N²-(tert-butoxycarbonyl)-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamineand 5-chloroindole-2-carboxylic acid in a similar manner to ReferentialExample 159.

[1644] 2)(1S,2R,4S)—N²-(tert-Butoxycarbonyl)-N¹-[(6-chloro-4-fluoroindol-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediaminewas treated with a 4N dioxane solution of hydrochloric acid and thencondensed with lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in asimilar manner to Example 118 to obtain the title compound.

[1645]¹H-NMR (DMSO-d₆) δ: 1.24-1.98(6H,m), 2.33-3.33(6H,m), 2.81(3H,s),2.90(3H,s), 2.99(3H,s), 4.12(1H,br.s), 4.30-4.70(1H,m), 4.60(1H,br.s),7.21(1H,s), 7.27(2H,br.s), 8.37(1H,d,J=8.1 Hz), 8.43(1H,d,J=7.6 Hz),12.11(1H,s). MS (FAB) m/z: 561(M+H)⁺.

Example 195(1S,2R,4S)—N¹-[(7-Chloroisoquinolin-3-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-N²-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediaminehydrochloride

[1646]

[1647](1S,2R,4S)—N²-(tert-Butoxycarbonyl)-N¹-[(7-chloroisoquinolin-3-yl)carbonyl]-4-(N,N-dimethyl-carbamoyl)-1,2-cyclohexanediaminewas treated with a saturated ethanol solution of hydrochloric acid andthen condensed with lithium5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in asimilar manner to Example 118 to obtain the title compound.

[1648]¹H-NMR (DMSO-d₆) δ: 1.45-1.65(1H,m), 1.70-1.85(3H,m),1.95-2.10(1H,m), 2.10-2.20(1H,m), 2.80(3H,s), 2.92(3H,s), 2.96(3H,s),2.95-3.10(1H,m), 3.10-3.40(3H,m), 3.70-3.80(1H,m), 4.20-4.30(1H,m),4.40-4.60(2H,m), 4.65-4.80(1H,m), 7.89(1H,m), 8.26(1H,d,J=8.8 Hz),8.38(1H,s), 8.60(1H,s), 8.85-9.00(2H,m), 9.33(1H,m). MS (FAB) m/z:555(M+H)⁺.

Test Example 1 Determination of FXa-inhibiting effect (IC₅₀ value)

[1649] Each specimen solution (10 μl), 100 mM Tris-200 mM sodiumchloride-0.2% BSA (pH 7.4) buffer (40 μl) and 0.05 U/ml human FXa(Cosmobio ERL HFXa-1011, dissolved and diluted with buffer formeasurement) (10 μl) were put on a 96-well microplate, and 750 μM S2222(Chromogenix Co.) (40 ml) was added to determine an increase (mOD/min)in absorbance at 405 nm at room temperature. The percent inhibition ofeach specimen was found in accordance with the following equation. Thefinal concentration of the specimen and the percent inhibition thereofwere plotted on the axis of abscissa and the axis of ordinate oflogarithmic normal probability paper, respectively, to determine themedian inhibition dose (IC₅₀).

Percent inhibition (%)=[1−(OD of specimen)÷(OD of control)]×100

[1650] (Result)

[1651] In the following table, it is demonstrated that the compoundsaccording to the present invention have a strong FXa-inhibiting effect.Compound FXa-inhibiting effect (IC₅₀) Example 3  86 nM Example 8  16 nMExample 10  83 nM Example 15  92 nM Example 41  36 nM Example 68 4.1 nMExample 70 2.7 nM Example 124 4.2 nM Example 143 3.5 nM Example 144 2.5nM Example 167 1.4 nM Example 176 3.3 nM

[1652] Industrial Applicability

[1653] The ethylenediamine derivatives according to the presentinvention exhibit a strong inhibitory effect on activated bloodcoagulation factor X and are useful as agents for preventing and/ortreating thrombotic diseases.

1. A compound represented by the general formula (1):Q¹-Q²-C(═O)—N(R¹)-Q³-N(R²)-T¹-Q⁴   (1) wherein R¹ and R², independentlyof each other, represent a hydrogen atom, hydroxyl group, alkyl group oralkoxy group; Q¹ represents a saturated or unsaturated, 5- or 6-memberedcyclic hydrocarbon group which may be substituted, a saturated orunsaturated, 5- or 6-membered heterocyclic group which may besubstituted, a saturated or unsaturated, bicyclic or tricyclic fusedhydrocarbon group which may be substituted, or a saturated orunsaturated, bicyclic or tricyclic fused heterocyclic group which may besubstituted; Q² represents a single bond, a linear or branched alkylenegroup having 1 to 6 carbon atoms, a linear or branched alkenylene grouphaving 2 to 6 carbon atoms, a linear or branched alkynylene group having2 to 6 carbon atoms, a group —N(R³)—, in which R³ means a hydrogen atomor alkyl group, a group —N(R⁴)—(CH₂)_(m)—, in which R⁴ means a hydrogenatom or alkyl group, and m is an integer of 1 to 6, a saturated orunsaturated, 5- or 6-membered divalent cyclic hydrocarbon group whichmay be substituted, a saturated or unsaturated, 5- or 6-membereddivalent heterocyclic group which may be substituted, a saturated orunsaturated, divalent bicyclic or tricyclic fused hydrocarbon groupwhich may be substituted, or a saturated or unsaturated, divalentbicyclic or tricyclic fused heterocyclic group which may be substituted;Q³ represents a group:

in which R⁵, R⁶, R⁷ and R⁸, independently of one another, mean ahydrogen atom, hydroxyl group, halogen atom, halogenoalkyl group, cyanogroup, cyanoalkyl group, acyl group, acylalkyl group, alkyl group,alkenyl group, alkynyl group, alkoxy group, alkoxyalkyl group,hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonylgroup, alkoxycarbonylalkyl group, carbamoyl group, N-alkylcarbamoylgroup, N,N-dialkyl-carbamoyl group, carbamoylalkyl group,N-alkylcarbamoylalkyl group, N,N-dialkylcarbamoylalkyl group, arylgroup, aralkyl group, heteroaryl group or heteroarylalkyl group, or thefollowing group:

in which Q⁵ means an alkylene group having 1 to 8 carbon atoms or analkenylene group having 2 to 8 carbon atoms, and R⁹ and R¹⁰ aresubstituents on carbon atom(s) of a ring comprising Q⁵ and areindependently of each other a hydrogen atom, hydroxyl group, alkylgroup, alkenyl group, alkynyl group, halogen atom, halogenoalkyl group,cyano group, cyanoalkyl group, amino group, aminoalkyl group,N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group,acylalkyl group, acylamino group which may be substituted, alkoxyiminogroup, hydroxyimino group, acylaminoalkyl group, alkoxy group,alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkylgroup, alkoxycarbonyl group, alkoxycarbonylalkyl group,alkoxycarbonylalkylamino group, carboxyalkylamino group,alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoylgroup, N-alkylcarbamoyl group which may have a substituent on the alkylgroup, N,N-dialkylcarbamoyl group which may have a substituent on thealkyl group, N-alkenyl-carbamoyl group, N-alkenylcarbamoylalkyl group,N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group,N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group,N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group,carbazoyl group which may be substituted by 1 to 3 alkyl groups,alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-memberednitrogen-containing heterocyclic carbonyl group which may besubstituted, carbamoylalkyl group, N-alkylcarbamoylalkyl group which mayhave a substituent on the alkyl group, N,N-dialkylcarbamoylalkyl groupwhich may have a substituent on the alkyl group, carbamoyloxyalkylgroup, N-alkylcarbamoyloxyalkyl group, N,N-dialkylcarbamoyl-oxyalkylgroup, 3- to 6-membered nitrogen-containing heterocycliccarbonyloxyalkyl group which may be substituted, 3- to 6-memberdnitrogen-containing heterocyclic carbonylalkyl group which may besubstituted, aryl group, aralkyl group, heteroaryl group,heteroarylalkyl group, alkylsulfonylamino group, arylsulfonylaminogroup, alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl group,alkylsulfonylaminocarbonyl group, arylsulfonylaminocarbonyl group,alkylsulfonyl-aminocarbonylalkyl group, arylsulfonylaminocarbonylalkylgroup, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxygroup, acyloxy group or acyloxyalkyl group, or R⁹ and R¹⁰, together witheach other, denote an alkylene group having 1 to 5 carbon atoms,alkenylene group having 2 to 5 carbon atoms, alkylenedioxy group having1 to 5 carbon atoms or carbonyldioxy group; Q⁴ represents an aryl groupwhich may be substituted, an arylalkenyl group which may be substituted,a heteroaryl group which may be substituted, a heteroarylalkenyl groupwhich may be substituted, a saturated or unsaturated, bicyclic ortricyclic fused hydrocarbon group which may be substituted, or asaturated or unsaturated, bicyclic or tricyclic fused heterocyclic groupwhich may be substituted; and T¹ represents a carbonyl or sulfonylgroup, a salt thereof, a solvate thereof, or an N-oxide thereof.
 2. Thecompound, the salt thereof, the solvate thereof, or the N-oxide thereofaccording to claim 1, wherein the group Q⁴ in the formula (1) is any oneof the following groups:

wherein R¹¹ and R¹², independently of each other, represent a hydrogenatom, cyano group, halogen atom, alkyl group, hydroxyalkyl group, alkoxygroup, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acylgroup, alkoxycarbonyl group, alkoxycarbonylalkyl group, or phenyl groupwhich may be substituted by a cyano group, hydroxyl group, halogen atom,alkyl group or alkoxy group; and R¹³ and R¹⁴, independently of eachother, represent a hydrogen atom, hydroxyl group, nitro group, cyanogroup, halogen atom, alkyl group, alkenyl group, alkynyl group,halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkylgroup, carboxyl group, carboxyalkyl group, carbamoyl group,alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group;

wherein R¹⁵, R¹⁶ and R¹⁷, independently of one another, represent ahydrogen atom, hydroxyl group, nitro group, cyano group, halogen atom,alkyl group, alkenyl group, alkynyl group, halogenoalkyl group,hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group,carboxyalkyl group, acyl group, carbamoyl group, alkoxycarbonyl group,amidino group or alkoxycarbonylalkyl group;

wherein X¹ represents CH₂, CH, NH, NOH, N, O or S; and R¹⁸, R¹⁹ and R²⁰,independently of one another, represent a hydrogen atom, hydroxyl group,nitro group, cyano group, halogen atom, alkyl group, alkenyl group,alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group,alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group,carbamoyl group, alkoxycarbonyl group, amidino group oralkoxycarbonylalkyl group;

wherein X² represents NH, N, O or S; X³ represents N, C or CH; X⁴represents N, C or CH; and R²¹ and R²², independently of each other,represent a hydrogen atom, hydroxyl group, nitro group, cyano group,halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkylgroup, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxylgroup, carboxyalkyl group, acyl group, carbamoyl group, alkoxycarbonylgroup, amidino group or alkoxycarbonylalkyl group; and

wherein N indicates that any one of carbon atoms of the ring substitutedby R²³ has been substituted by a nitrogen atom; and R²³, R²⁴ and R²⁵,independently of one another, represent a hydrogen atom, hydroxyl group,nitro group, cyano group, halogen atom, alkyl group, alkenyl group,alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group,alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group,carbamoyl group, alkoxycarbonyl group, amidino group oralkoxycarbonylalkyl group.
 3. The compound, the salt thereof, thesolvate thereof, or the N-oxide thereof according to claim 1 or 2,wherein the group Q⁴ in the formula (1) is

wherein R¹¹, R¹² and R¹³ are all hydrogen atoms, and R¹⁴ is a halogenatom or ethynyl group;

wherein R¹⁵ and R¹⁶ are both hydrogen atoms, and R¹⁷ is a halogen atomor ethynyl group;

wherein X¹ is NH, NOH, N, O or S, R¹⁸ is a hydrogen atom, R¹⁹ is ahydrogen or halogen atom, and R²⁰ is a halogen atom, alkyl or ethynylgroup;

wherein X² is NH, O or S, X³ is N, C or CH, X⁴ is N, C or CH, R²¹ is ahydrogen atom, and R²² is a halogen atom or ethynyl group; or

wherein N indicates that any one of carbon atoms of the ring substitutedby R²³ has been substituted by a nitrogen atom, and R²³ and R²⁴ are bothhydrogen atoms, and R²⁵ is a cyano group, halogen atom, alkyl group,alkenyl group, alkynyl group or halogenoalkyl group.
 4. The compound,the salt thereof, the solvate thereof, or the N-oxide thereof accordingto any one of claims 1 to 3, wherein the group Q¹ in the formula (1) isa saturated or unsaturated, bicyclic or tricyclic fused hydrocarbongroup which may be substituted, or a saturated or unsaturated, bicyclicor tricyclic fused heterocyclic group which may be substituted; and thegroup Q² is a single bond.
 5. The compound, the salt thereof, thesolvate thereof, or the N-oxide thereof according to any one of claims 1to 4, wherein the group Q¹ in the formula (1) is a thienopyridyl groupwhich may be substituted, tetrahydrothienopyridyl group which may besubstituted, thiazolopyridyl group which may be substituted,tetrahydrothiazolopyridyl group which may be substituted,thiazolopyridazinyl group which may be substituted,tetrahydrothiazolopyridazinyl group which may be substituted,pyranothiazolyl group which may be substituted, dihydropyranothiazolylgroup which may be substituted, furopyridyl group which may besubstituted, tetrahydrofuropyridyl group which may be substituted,oxazolopyridyl group which may be substituted, tetrahydrooxazolopyridylgroup which may be substituted, pyrrolopyridyl group which may besubstituted, dihydropyrrolopyridyl group which may be substituted,tetrahydropyrrolopyridyl group which may be substituted,pyrrolopyrimidinyl group which may be substituted,dihydropyrrolopyrimidinyl group which may be substituted,oxazolopyridazinyl group which may be substituted,tetrahydrooxazolopyridazinyl group which may be substituted,pyrrolothiazolyl group which may be substituted, dihydropyrrolothiazolylgroup which may be substituted, pyrrolooxazolyl group which may besubstituted, dihydropyrrolooxazolyl group which may be substituted,benzothiazolyl group which may be substituted, tetrahydrobenzothiazolylgroup which may be substituted,4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl group which maybe substituted, or5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl group which maybe substituted; and the group Q² is single bond.
 6. The compound, thesalt thereof, the solvate thereof, or the N-oxide thereof according toany one of claims 1 to 3, wherein the group Q¹ in the formula (1) is asaturated or unsaturated, 5- or 6-membered cyclic hydrocarbon groupwhich may be substituted, or a saturated or unsaturated, 5- or6-membered heterocyclic group which may be substituted; and the group Q²is a saturated or unsaturated, 5- or 6-membered divalent cyclichydrocarbon group which may be substituted, or a saturated orunsaturated, 5- or 6-membered divalent heterocyclic group which may besubstituted.
 7. The compound, the salt thereof, the solvate thereof, orthe N-oxide thereof according to any one of claims 1 to 6, wherein thegroup Q³ in the formula (1) is

wherein Q⁵, R⁹ and R¹⁰ have the same meanings as defined above.
 8. Thecompound, the salt thereof, the solvate thereof, or the N-oxide thereofaccording to any one of claims 1 to 7, wherein the group T¹ in theformula (1) is a carbonyl group.
 9. The compound, the salt thereof, thesolvate thereof, or the N-oxide thereof according to any one of claims 1to 8, wherein the group Q⁴ in the formula (1) is a 4-chlorostyryl,4-fluorostyryl, 4-bromostyryl, 4-ethynylstyryl, 6-chloro-2-naphthyl,6-fluoro-2-naphthyl, 6-bromo-2-.naphthyl, 6-ethynyl-2-naphthyl,7-chloro-2-naphthyl, 7-fluoro-2-naphthyl, 7-bromo-2-naphthyl,7-ethynyl-2-naphthyl, 5-chloroindol-2-yl, 5-fluoroindol-2-yl,5-bromoindol-2-yl, 5-ethynylindol-2-yl, 5-methylindol-2-yl,5-chloro-4-fluoroindol-2-yl, 6-chloroindol-2-yl, 6-fluoroindol-2-yl,6-bromoindol-2-yl, 6-ethynylindol-2-yl, 6-methyllindol-2-yl,5-chlorobenzothiophen-2-yl, 5-fluorobenzothiophen-2-yl,5-bromobenzothiophen-2-yl, 5-ethynylbenzothiophen-2-yl,5-methylbenzothiophen-2-yl, 5-chloro-4-fluoro-benzothiophen-2-yl,6-chlorobenzothiophen-2-yl, 6-fluorobenzothiophen-2-yl,6-bromobenzothiophen-2-yl, 6-ethynylbenzothiophen-2-yl,6-methylbenzothiophen-2-yl, 5-chlorobenzofuran-2-yl,5-fluorobenzofuran-2-yl, 5-bromobenzofuran-2-yl,5-ethynylbenzofuran-2-yl, 5-methylbenzofuran-2-yl,5-chloro-4-fluorobenzofuran-2-yl, 6-chlorobenzofuran-2-yl,6-fluorobenzofuran-2-yl, 6-bromobenzofuran-2-yl,6-ethynylbenzofuran-2-yl, 6-methylbenzofuran-2-yl,6-chloroquinolin-2-yl, 6-fluoroquinolin-2-yl, 6-bromoquinolin-2-yl,6-ethynylquinolin-2-yl, 7-chloroquinolin-3-yl, 7-fluoroquinolin-3-yl,7-bromoquinolin-3-yl, 7-ethynylquinolin-3-yl, 7-chloroisoquinolin-3-yl,7-fluoroisoquinolin-3-yl, 7-bromoisoquinolin-3-yl or7-ethynylisoquinolin-3-yl group.
 10. The compound, the salt thereof, thesolvate thereof, or the N-oxide thereof according to any one of claims 1to 9, wherein the group Q³ in the formula (1) is

wherein n is an integer of 1 to 8, R⁹ is a hydrogen atom, and R¹⁰ is ahydrogen atom, hydroxyl group, alkyl group, halogen atom, hydroxyiminogroup, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group,acylamino group which may be substituted, acylaminoalkyl group, alkoxygroup, alkoxyalkyl group, hydroxyalkyl group, carboxyl group,alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylaminogroup, carbamoyl group, N-alkylcarbamoyl group which may have asubstituent on the alkyl group, N,N-dialkylcarbamoyl group which mayhave a substituent on the alkyl group, N-alkenylcarbamoyl group,N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group,N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group,N-alkyl-N-alkoxycarbamoyl group, N-alkyl-N-alkoxy-carbamoylalkyl group,carbazoyl group which may be substituted by 1 to 3 alkyl groups,alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-memberednitrogen-containing heterocyclic carbonyl group which may besubstituted, 3- to 6-membered nitrogen-containing heterocycliccarbonyloxyalkyl group which may be substituted, carbamoylalkyl group,N,N-dialkylcarbamoyloxyalkyl group, N-alkylcarbamoylalkyl group whichmay have a substituent on the alkyl group, N,N-dialkylcarbamoylalkylgroup which may have a substituent on the alkyl groups,alkylsulfonylamino group, alkylsulfonylaminoalkyl group, oxo group oracyloxy group.
 11. A medicine comprising the compound, the salt thereof,the solvate thereof, or the N-oxide thereof according to any one ofclaims 1 to 10 as an active ingredient.
 12. An activated bloodcoagulation factor X inhibitor comprising the compound, the saltthereof, the solvate thereof, or the N-oxide thereof according to anyone of claims 1 to 10 as an active ingredient.
 13. An anticoagulantcomprising the compound, the salt thereof, the solvate thereof, or theN-oxide thereof according to any one of claims 1 to 10 as an activeingredient.
 14. An agent for preventing and/or treating thrombosis orembolism, comprising the compound, the salt thereof, the solvatethereof, or the N-oxide thereof according to any one of claims 1 to 10as an active ingredient.
 15. An agent for preventing and/or treatingcerebral infarction, cerebral embolism, myocardial infarction, anginapectoris, pulmonary infarction, pulmonary embolism, Buerger's disease,deep venous thrombosis, disseminated intravascular coagulation syndrome,thrombus formation after valve or joint replacement, thrombus formationand reocclusion after angioplasty, systemic inflammatory reactionsyndrome (SIRS), multiple organ disease syndrome (MODS), thrombusformation during extracorporeal circulation, or blood clotting uponblood gathering.
 16. A medicinal composition comprising the compound,the salt thereof, the solvate thereof, or the N-oxide thereof accordingto any one of claims 1 to 10, and a pharmaceutically acceptable carrier.17. Use of the compound, the salt thereof, the solvate thereof, or theN-oxide thereof according to any one of claims 1 to 10 for preparationof a medicine.
 18. A method for treating thrombosis or embolism, whichcomprises administering the compound, the salt thereof, the solvatethereof, or the N-oxide thereof according to any one of claims 1 to 10.19. A method for treating cerebral infarction, cerebral embolism,myocardial infarction, angina pectoris, pulmonary infarction, pulmonaryembolism, Buerger's disease, deep venous thrombosis, disseminatedintravascular coagulation syndrome, thrombus formation after valve orjoint replacement, thrombus formation and reocclusion after angioplasty,systemic inflammatory reaction syndrome (SIRS), multiple organ diseasesyndrome (MODS), thrombus formation during extracorporeal circulation,or blood clotting upon blood gathering, which comprises administeringthe compound, the salt thereof, the solvate thereof, or the N-oxidethereof according to any one of claims 1 to
 10. 20. A compoundrepresented by the following general formula (4): HN(R¹)-Q³-N(R²)-T¹-Q⁴  (4) wherein R¹, R² and T¹ have the same meanings as defined above, Q⁴represents a saturated or unsaturated, bicyclic or tricyclic hydrocarbongroup which may be substituted, or a saturated or unsaturated, bicyclicor tricyclic fused heterocyclic group which may be substituted; and Q³represents

wherein Q⁵, R⁹ and R¹⁰ have the same meanings as defined above, a saltthereof, a solvate thereof, or an N-oxide thereof.
 21. A compoundrepresented by the following general formula (9):Q¹-Q²-C(═O)—N(R¹)-Q³-NHR²   (9) wherein R¹ and R² have the same meaningsas defined above, Q¹ represents a saturated or unsaturated, bicyclic ortricyclic heterocyclic group which may be substituted, Q² represents asingle bond, and Q³ represents

in which Q⁵, R⁹ and R¹⁰ have the same meanings as defined above, a saltthereof, a solvate thereof, or an N-oxide thereof.